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Elke Gurschke Page 1 of 126

Best Practice Guide for Regulatory Affairs in a German CRO


From Application to Clinical Trial Report: Implications of Well-Structured Completion of Relevant Steps

Wissenschaftliche Prüfungsarbeit

zur Erlangung des Titels

„Master of Drug Regulatory Affairs“

der Mathematisch-Naturwissenschaftlichen Fakultät

der Rheinischen Friedrich-Wilhelms-Universität Bonn

vorgelegt von

Elke Gurschke

aus Düsseldorf

Bonn, 2011



Betreuerin und 1. Referentin: Frau Dr. Ingrid Klingmann

Zweiter Referent: Herr Dr. Bob Wilffert



Preface

The idea for this master thesis came to my mind while recently discussing with a client

of our institute about the necessity of notifying a substantial amendment of a clinical

trial to the responsible local authority (LA). Even in large pharmaceutical companies,

there is sometimes only poor knowledge about the regulatory requirements of the

application process and as well during the conduct of a clinical trial for trials conducted

in Germany. Guidance documents, e.g. of the European Community, may serve as

road signs for what will be needed, but reality differs quite a lot, especially when dealing

with Ethics Committees (ECs), and therefore a “Best Practice Guide” may help to find a

way through the regulatory jungle.

In my daily work as Regulatory Affairs Manager in a CRO in Neuss, Germany, I

normally have to deal with the Federal Institute for Drugs and Medical Devices

[Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM)] in Bonn, Germany, as

responsible competent authority (CA) due to our specialisation on medicinal products

for the treatment of diabetes. The responsible Ethics Committee is the Ethics

Committee of the Medical Association North Rhine (Ethikkommission der Ärztekammer

Nordrhein) in Düsseldorf, Germany, as long as we are conducting mono-centre trials or

multi-centre trials as leading site.

Very often, our regulatory department will only do the application for authorisation of a

clinical trial to the EC, whereas in most cases the submission of the relevant documents

to BfArM remains in the responsibility of the sponsor. This may be subject to those

documents, which contain manufacturing details, and company secrets not dedicated to

be given to people not belonging to that company. Although non-disclosure agreements

are in place on a regular basis, most companies probably prefer not to reveal more

details about their product than necessary. IB (Investigator’s Brochure) and protocol

must be submitted to EC as well, but the IMPD – the (more or less complete) dossier of

the investigational product – contains of detailed information in connection with the

product and will only be submitted to BfArM.

According to § 42(1) German Drug Law (Arzneimittelgesetz – AMG), the responsibility

of the EC results from the trial site in which the principal investigator (PI) for the

respective trial is situated. The PI is responsible for the conduct of the trial at this very



trial site according to the local laws and regulations, e.g. GCP Ordinance, Drug Law,

and in agreement with the protocol, and other relevant documents. For mono-centre

trials, this allocation is clearly defined, but in multi-centre trials each trial site has a

principal investigator. In this case, a so-called coordinating investigator must be chosen

and “his” or “her” EC will act as leading EC whereas all other participating ECs are

mainly responsible for the evaluation of the suitability of the trial site(s) belonging to that

EC. The leading EC, however, is supposed to assess the clinical trial after consultation

with the participating ECs.

In order not to complicate the following deliberations, I will mainly refer to requirements

for a mono-centre trial for which our department is responsible for applications to both

EC (here: Ethics Committee of the Medical Association North Rhine) and CA (here:

BfArM).

The responsibility of the local authority(ies) as further actor in the regulatory scenery

according to § 67 AMG and § 12 GCP Ordinance is well described through the

localisation of the trial site. In Germany, several local authorities are in place and may

be found on the website of the Central Authority of the Länder for Health Protection with

regard to Medicinal Products and Medical Devices (Zentralstelle der Länder für

Gesundheitsschutz bei Arzneimitteln und Medizinprodukten – ZLG). In our case, we

have to notify trial activities to the Inspectorate for clinical trial sites in North Rhine-

Westphalia (Inspektorat für klinische Prüfstellen in Nordrhein-Westfalen) and / or to the

Regional Council (Bezirksregierung), both situated in Düsseldorf. The Inspectorate is

responsible for the monitoring of all trial sites in the federal state, including universities,

whereas the Regional Council has to observe activities of other parties, such as

laboratories and CROs. If our pharmacy is performing manufacturing activities for the

respective trial, or if we carry out other activities, which fall within the responsibilities of

a contract research organisation, e.g. application to EC or BfArM, we have to notify to

both authorities – which is the norm for trials conducted at our institute.

Anyone who is dealing with Paul-Ehrlich-Institute, the Federal Institute for Vaccines and

Biomedicines (Paul-Ehrlich-Institut, Bundesinstitut für Impfstoffe und biomedizinische

Arzneimittel) in Langen, Germany, instead of BfArM, one of the other German ECs or

other LAs may have experienced divergent formal requirements, various contents of



deficiency letters, and different ways of communication – the comparison of these

differences may be subject to another master thesis.

Please note: In the course of this master thesis, German expressions will be written in

italics.



Table of Contents

Page

1 INTRODUCTION.................................................................................................12 1.1 LEGAL BASIS .................................................................................................................. 12 1.2 LOCAL REQUIREMENTS................................................................................................... 15

2 INITIAL APPLICATION ......................................................................................16 2.1 RESPONSIBILITIES .......................................................................................................... 16 2.2 FIRST STEPS.................................................................................................................. 16 2.3 TIMELINES AND FORMAL REQUIREMENTS ........................................................................ 17 2.4 REQUIRED DOCUMENTS.................................................................................................. 20 2.5 DEFICIENCIES................................................................................................................. 58 2.6 NOTIFICATION ACCORDING TO § 67 AMG ........................................................................ 68

3 REQUIREMENTS DURING THE TRIAL ............................................................73 3.1 AMENDMENTS ................................................................................................................ 73 3.2 AE AND SUSAR REPORTING.......................................................................................... 82 3.3 IB UPDATE ..................................................................................................................... 84 3.4 YEARLY REPORT ............................................................................................................ 85

4 END OF TRIAL NOTIFICATION.........................................................................87 4.1 RESPONSIBILITIES .......................................................................................................... 87 4.2 TIMELINES AND FORMAL REQUIREMENTS ........................................................................ 87 4.3 REQUIRED DOCUMENTS.................................................................................................. 88

5 REPORT .............................................................................................................90 5.1 TIMELINES AND FORMAL REQUIREMENTS ........................................................................ 91

6 HELPERS IN DAILY WORK...............................................................................93 6.1 LIST OF DOCUMENTS ...................................................................................................... 93 6.2 STRUCTURE OF FOLDERS................................................................................................ 94 6.3 FILENAMES..................................................................................................................... 99 6.4 TEMPLATES.................................................................................................................. 105 6.5 FAQ LIST ..................................................................................................................... 107 6.6 TODO-CLIENT .............................................................................................................. 108 6.7 MISCELLANEOUS .......................................................................................................... 112

7 CONCLUSION AND OUTLOOK ......................................................................113 8 SUMMARY........................................................................................................117 9 REFERENCES..................................................................................................119 10 APPENDICES...................................................................................................125



List of Abbreviations

AMG Arzneimittelgesetz (German Drug Law / German Medicinal Products Act)

ASR Annual Safety Report

BfArM Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute for

Drugs and Medical Devices)

CA Competent Authority

CIOMS Council for International Organizations of Medical Sciences

CRO Contract Research Organisation

CTD Common Technical Document

EC Ethics Committee

EEA European Economic Area

EFGCP European Forum for Good Clinical Practice

EU European Union

EudraCT European Union Drug Regulating Authorities Clinical Trials

GCP Good Clinical Practice

GCP-V Verordnung über die Anwendung der Guten Klinischen Praxis bei der

Durchführung von klinischen Prüfungen mit Arzneimitteln zur Anwendung

am Menschen (German GCP Ordinance)

IB Investigator’s Brochure

ICH International Conference on Harmonisation of Technical Requirements for

Registration of Pharmaceuticals for Human Use

IMP Investigational Medicinal Product

IMPD Investigational Medicinal Product Dossier

LA Local Authority



PEI Paul-Ehrlich-Institut – Bundesinstitut für Impfstoffe und biomedizinische

Arzneimittel (Paul-Ehrlich-Institute – the Federal Institute for Vaccines and

Biomedicines)

PI Principal Investigator

PIC Participant Informed Consent Form

PIS Participant Information Sheet

QP Qualified Person

RAM Regulatory Affairs Manager

SOP Standard Operating Procedure

SUSAR Suspected Unexpected Serious Adverse Reaction

TIF Trial Investigator File

TSE Transmissible Spongiform Encephalopathy

ZLG Zentralstelle der Länder für Gesundheitsschutz bei Arzneimitteln und

Medizinprodukten (Central Authority of the Länder for Health Protection

with regard to Medicinal Products and Medical Devices)



List of Figures

Figure 1: Review period EC / Best case.................................................................................. 18

Figure 2: Review period EC / Worst case ............................................................................... 18

Figure 3: Review period BfArM / Best case............................................................................. 19

Figure 4: Review period BfArM / Best case............................................................................. 19

Figure 5: Welcome Page; EudraCT (Public Site) .................................................................... 40

Figure 6: Get Security Code; EudraCT (Public Site) ............................................................... 41

Figure 7: Get EudraCt Number; EudraCT (Public Site)........................................................... 42

Figure 8: Initial Required Information; EudraCT (Public Site) ................................................. 43

Figure 9: Main Menu Page; EudraCT (Public Site) ................................................................. 48

Figure 10: Load Application from File; EudraCT (Public Site)................................................. 49

Figure 11: Validate Application Results with Failures; EudraCT (Public Site)......................... 50

Figure 12: Failures in Section E; EudraCT (Public Site) ......................................................... 51

Figure 13: Validate Application Results without Failures; EudraCT (Public Site).................... 52

Figure 14: Labeltext “Primary and secondary packaging”....................................................... 56

Figure 15: Labeltext “Primary packaging if primary / secondary packaging remain together” 57

Figure 16: Labeltext “Primary packaging for blisters or small units”........................................ 57

Figure 17: Structure of folders “Authorities” ............................................................................ 94

Figure 18: Structure of folders “BfArM” ................................................................................... 94

Figure 19: Structure of folders “BfArM / Amendments” ........................................................... 95

Figure 20: Structure of folders “BfArM / Documents for submission” ...................................... 95

Figure 21: Structure of folders “EC” ........................................................................................ 96

Figure 22: Structure of folders “EC / Amendments” ................................................................ 97

Figure 23: Structure of folders “EC / Documents for submission” ........................................... 97

Figure 24: Structure of folders “Inspectorate”.......................................................................... 98

Figure 25: Structure of folders “Regional Council” .................................................................. 98



Figure 26: Structure of folders “Insurance”.............................................................................. 99

Figure 27: Structure of folders and files “EC” ........................................................................ 104

Figure 28: Templates for documents “EC” ............................................................................ 105

Figure 29: Templates for documents “BfArM” ....................................................................... 106

Figure 29: Templates for documents “Inspectorate” ............................................................. 106

Figure 30: Templates for documents “Regional Council” ...................................................... 106

Figure 31: Templates for documents “Insurance” ................................................................. 107

Figure 32: FAQ list “BfArM” ................................................................................................... 107

Figure 33: FAQ list “EC” ........................................................................................................ 107

Figure 34: Screenshot of the ToDo Client for an exemplarily trial ......................................... 109

Figure 35: Screenshot of the trial statistics from 01 January to 29 December 2010............. 111



List of Tables

Table 1: Section F of “Notification of a substantial amendment form” ..................................... 76

Table 2: Filenames for correspondence “EC”........................................................................ 100

Table 3: Filenames for correspondence “BfArM”................................................................... 101

Table 4: Filenames for correspondence “Inspectorate” ......................................................... 102

Table 5: Filenames for correspondence “Regional Council”.................................................. 102

Table 6: Filenames for correspondence “Insurance company” ............................................. 103



1 Introduction

1.1 Legal Basis

Clinical trials are relevant parts of the development and for the marketing authorisation

of medicinal products, as well as after authorisation, to gain further knowledge about

the product. After implementation of the Declaration of Helsinki in 1964 [43], with its

sixths revision in October 2008, and the Guideline for Good Clinical Practice of the

International Conference on Harmonization [27] (ICH, Topic E6) as of 17 July 1996,

last amended in July 2002 [28], basic principles considering the latest scientific and

safety developments have been laid down for the safeguard of trial participants, and

the correct designing, conducting, recording and reporting of trials to achieve at last

credible and reliable data.

As of 4 April 2001, the basic principles for the conduct of clinical trials have been laid

down in Directive 2001/20/EC [11] of the European Parliament and of the Council, the

so-called “Clinical Trials Directive”. These principles should approximate laws,

regulations, and administration of the Member States of the European Union, and

result in the implementation of good clinical practice in the conduct of clinical trials

throughout the EU. Through a profound risk assessment of the results of preclinical

investigations and previously conducted clinical trials by the Ethics Committees and

the relevant competent authorities of the respective Member State, it should be

guaranteed that the safety and well-being of the trial participants, and the preservation

of their very own data will be protected in every respect. Further substantiation was

gained by the implementation of the “GCP Directive”, the Commission Directive

2005/28/EC [4], with principles and detailed guidelines for good clinical practice for

clinical trials in humans. Requirements for the aspects of manufacturing and/or

importation of investigational medicinal products can also be found in this Directive.

For clinical trials, which are conducted outside the EU but their results should be

implemented in an application for marketing authorisation of a medicinal product within

the EU, Annex I Part 4 of Directive 2001/83/EC [12] must be considered.



Of main importance was the implementation of Directive 2001/20/EC [11] for the

conduct of multinational, multi-centre clinical trials, due to the previous difference of

action regarding the conduct of clinical trials within the EU. To facilitate information

flow between all Member States, a European databank had been established –

EudraCT (European Union Drug Regulating Authorities Clinical Trials) [15] – within the

European Medicines Agency (EMA). EudraCT contains of information from all clinical

trials from 1st May 2004 onwards. At present, EudraCT Version 7.0 is used for the

application form, whereas Version 8.0 should have been released in October 2010,

but the start of the new version was postponed to a later date (now expected to be

activated on 10 March 2011) due to the complexity of the final steps of

implementation. Access is granted for the competent authorities of all Member States,

and the use of the public website of this databank is obligatory as sponsor interface for

applications of authorisation of a clinical trial. A detailed guidance [10], a manual for

users [16], and a list of frequently asked questions [14] regarding the functionality of

this database should enable all users to make efficiently use of the application

documents.

EudraLex, Volume 10 – Clinical trials guidelines [20], should serve as collection of

superior European regulations, guidelines, and guidances. Of great help for the

understanding of the application procedure is Chapter 1: “Application and Application

Form” with detailed guidance documents for the request for authorisation of a clinical

trial, notification of substantial amendments, and declaration of the end of the trial to

the competent authorities [7], for application for an Ethics Committee opinion [8], and

on the EudraCT clinical trials database [10].

The European Directive [11] had been transferred into German law in August 2004

with the 12th amendment of the German Drug Law – AMG (12. AMG-Novelle).

Consequently, a few days later the German GCP Ordinance (GCP-Verordnung) [41]

had been established as guidance document for the conduct of clinical trials with

medicinal products in humans, which was last amended in November 2006. Since

then, a clinical trial must not be conducted without having received a positive opinion

of the responsible Ethics Committee, and an approval (explicitly or implicitly,

depending on the nature of the medicinal product) of the competent authority. The 14th



amendment of the German Drug Law was the national adoption of Directive

2001/83/EC [12], and meanwhile, the 15th amendment of the German Drug Law (15.

AMG-Novelle) [22] is effective as of July 2009.

Of the German Drug Law [22], especially the articles 40-42a have to be considered for

the application for authorisation of a clinical trial, whereas for example articles 1 to 4

provide aim and scope of this law, and as well definitions.

The GCP Ordinance [41] must be considered in total, and provides general provisions

for all participants of the authorisation process, such as applicant, competent

authority, Ethics Committee, and local authorities.

Information to the application process, required documents, and the timelines may

also be obtained through the websites of the relevant parties, e.g. either PEI or BfArM

for the competent authorities in Germany, the Central Authority of the Länder for

Health Protection with regard to Medicinal Products and Medical Devices – ZLG for

the local authorities, and the Working Group of the Medical Ethics Committees in

Germany (in the following called EC Working Group), or their own websites,

respectively, for the Ethics Committees (cave: the Ethics Committee of the Medical

Association North Rhine is not part of this EC Working Group, may have different

views of relevant topics and may therefore not follow the recommendations of the EC

Working Group). For applications to BfArM or PEI especially the joint 3rd notification [1]

is of great help for understanding the specific requirements.

The review of any application or amendment in the course of the trial will be charged

according to the scales of fees and charges of the respective institution. For BfArM the

attachment of the AMGKostV [32] has to be considered (e.g. between 1,500 and

3,700 EUR for the process of authorisation of a clinical trial). For the review of the

Ethics Committee, charges may be identified through the website of the respective EC

– they may differ in each case. For the local authorities, the cost laws and cost

ordinances of the respective federal state apply. For North Rhine-Westphalia these

are Gebührengesetz für das Land Nordrhein-Westfalen (GebG NRW) [21] and

Allgemeine Verwaltungsgebührenordnung (AVerwGebO NRW) [2], with fees between

25 EUR and 250 EUR for checking and confirming the notification of the conduct of or

amendments to a clinical trial according to § 67 German Drug Law [22].



1.2 Local Requirements

As already to some extent described in the preface, a regulatory department is

mandatory for a CRO, which is not only dealing with the conduct, but also with

applications for authorisation of clinical trials. While communicating with the several

involved parties, more and more expertise is gained, and herewith the application

process will become easier in the process of time and (at least formal) mistakes can

be more and more avoided. However, especially in case of the Ethics Committee with

changing composition of its members, you will never be sure to have all documents in

order, but in most cases it can only be an approach to an application without any

failures or contentual deficiencies.

A regulatory department must at least contain of two responsible persons who should

work together on a regular basis, and who can substitute each other in case of

holidays or illness. In our case, a third employee serves as back-up, and is always

copied in the relevant e-mails, is part of the fax group for all faxes coming from the

authorities and the Ethics Committee, and so receives all necessary information to be

able to step in just in case.

The qualification to work as a Regulatory Affairs Manager should be a profound

scientific training with focus on at least basic medical knowledge, e.g. Physician,

Pharmacist, Biologist, Nutritionist, or possibly a Nurse or Doctor’s Assistant with good

skills in English, interest in administrative activities, and ability to well-structured and

accurate work. Communicative skills are very relevant as well, since more or less

regular consultations with the involved parties will occur. For the study teams, it is

more than helpful in the beginning of the application process that the regulatory

department is able to discuss important issues directly with employees of the sponsor

(mostly in English) and, of course, with the regulatory authorities.



2 Initial Application

2.1 Responsibilities

The responsibility to apply for a clinical trial authorisation remains with the sponsor

according to § 7 GCP Ordinance [41] – nevertheless, the sponsor may delegate the

application to a third party, ideally an experienced CRO. For this purpose, a letter of

authorisation should be created to clarify this delegation to the authorities.

Additionally, a responsibility split list (which is normally part of the contract between

the parties) should be added to the EC submission package to identify the

responsibilities regarding relevant duties.

If the sponsor’s place of business is not situated within the European Union or another

state of the European Economic Area – EEA – which are, in addition to the EU

Member States, Norway, Liechtenstein, and Iceland, a legal representative within the

EEA must be available who will be legally responsible for all trial activities instead of

the sponsor. To clearly identify these duties, a letter of authorisation from the sponsor,

and as well a responsibility confirmation letter of the representative should be

submitted to avoid inquiries of EC and BfArM.

2.2 First Steps

To be able to submit the application for a clinical trial authorisation, it will be necessary

to identify the concerned EC and CA, and to clarify the local requirements in form and

content. Neither the European directives nor the local implementations in Germany,

GCP-V [41] and AMG [22], give detailed information about the format and quantity of

the documents that have to be submitted. As outlined before, the nature of the

investigational medicinal product defines the responsibility of the competent authority

– BfArM or PEI – whereas the EC will be determined through the investigational site in

which the principal investigator for mono-centre trials or the coordinating investigator

for multi-centre trials, respectively, is situated.



The BfArM requirements may be detected easily by visiting the website, and reading

the relevant documents, or just by calling the secretary, but for EC requirements it is

much more difficult to find out what is really required – despite any recommendations,

e.g. from the EC Working Group, each EC seems to have their own way to deal with

the submissions. For the Ethics Committee of the Medical Association North Rhine,

the requirements will be specified in the following.

2.3 Timelines and Formal Requirements

2.3.1 Ethics Committee

The timelines for the review process in all German ECs are presented in the GCP-V

[41]. For the first review period, there are 30 days for mono-centre and 60 days for

multi-centre trials. After receipt of the application package, a clerk will check the

documents formally. If anything is missing, a letter stating formal deficiencies will be

sent to the applicant within 10 days. The applicant has 14 days to answer these

deficiencies – the review period does not begin until a formal correct application has

arrived at the EC. To avoid any delay in the application process, we therefore always

try to manage a formal complete submission on the first attempt.

If there are any contentual deficiencies – and usually there are some, mainly in the

participant information sheet – the review period stops by sending the corresponding

notification to the applicant. Since the EC has 30 days overall to give their vote, the

notification of contentual deficiency will be sent about day 20-22 of the whole review

period. In this so called “stop clock period” the applicant now has to reply to the

deficiencies – either by implementing them into the relevant documents or by

defending his position.

After resending the answer to the raised deficiencies, the remaining review period

starts, and the final opinion will be sent after a total of 30 days.

In the following overview, two scenarios are presented: on the one hand a formal

complete submission without contentual deficiencies as best case, on the other hand

an application with formal and contentual deficiencies as worst case scenario.



Best case

Day after submission = day 1 = start of review period no formal deficiencies

no contentual deficiencies positive opinion on day 30

day 1 day 30

Figure 1: Review period EC / Best case

Worst case

Day after submission = day 1 notification of formal deficiencies on day 10

answer to deficiencies 14 days later (at the latest) = start of review period ca. on

day 44: contentual deficiencies clock stop / e.g. 30 days to answer to deficiencies

restart of review period on day 74 positive opinion on day 84

day 1 day 10 day 24 ca. day 44 day 74 day 84

Figure 2: Review period EC / Worst case

All documents will have to be submitted ninefold in folders, and we always use an

index in each folder to facilitate the review for the EC members. The files will have to

be saved on a CD ROM as well, either as pdf file or – in the case of the application

form – as xml file.

It is of great importance that the EC vote will be given explicitly – which means that the

applicant must not start the trial without a definite favourable opinion in writing.

2.3.2 BfArM

In general, the documents for BfArM will have to be submitted similar to the

documents for the EC – in good order, clearly structured and not only as paper copies

(fourfold) but also on CD ROM as pdf and xml files. After a formal complete

submission – in case of formal deficiencies the same timelines as with EC apply – the

review time is also 30 days. In case of contentual deficiencies, however, the timelines

are a bit different because the applicant will receive the notification letter after 30 days,



and will have to respond within 90 days. In case the deficiencies cannot be answered

timely, the application will be rejected, but a resubmission may be conducted at a later

stage. After answering within the timeline, BfArM has another 15 days to approve or

disapprove the application. Therefore, in case of contentual deficiencies the BfArM

review time is 45 days altogether, whereas for the EC it remains at 30 days.

Best case

Day after submission = day 1 = start of review period no formal deficiencies

no contentual deficiencies approval on day 30

day 1 day 30

Figure 3: Review period BfArM / Best case

Worst case

Day after submission = day 1 notification of formal deficiencies on day 10

answer to deficiencies 14 days later (at the latest) = start of review period on day

54: contentual deficiencies 90 days to answer to deficiencies 15 days review

period of answer approval on day 45 of review period = 159 days

day 1 day 10 day 24 day 54 … … day 144 day 159

… …

Figure 4: Review period BfArM / Best case

For BfArM an implicit vote will be sufficient in many cases – which means that the trial

may begin after the deadline of the review period, if BfArM “has not raised grounds of

non-acceptance”, according to Directive 2001/20/EC [11], and no contentual

deficiencies have been observed. Nevertheless, normally BfArM will send an approval

letter, though. If an implicit authorisation is impossible, BfArM will inform the applicant

accordingly in the written confirmation of receipt of a formal correct submission. This is

subject to the nature of the IMP according to § 42(2) sentence 7, no. 1 AMG [22] in

connection with no. 1 and 1a of the Annex of Regulation (EC) No 726/2004.



For example in case of insulin, which is manufactured by means of recombinant DNA

technology, the authorisation will be given explicitly within the given deadline of 30

days.

According to this regulation, this is the fact also for all other “Medicinal products

developed by means of one of the following biotechnological processes:

• recombinant DNA technology,

• controlled expression of genes coding for biologically active proteins in

prokaryotes and eukaryotes including transformed mammalian cells,

• hybridoma and monoclonal antibody methods.” [37]

2.4 Required Documents


Cover Letter

The cover letter is the first document in the submission package, but the last one that

should be finished. All submitted documents should be listed with date and version,

and the letter should contain of the EudraCT number, the title, and the protocol ID. In

our cover letters, this information is placed right below the subject line, and will be

used, together with the serial number of the EC, for all subsequent letters to the EC

(e.g. answers to contentual deficiencies, amendments or notifications).

Because last minute changes occur very often, the cover letter cannot be considered

final before all other documents are ready. It happened not only once that in the last

review of the submission package by one of our project managers (they have to finally

release all files) one or more mistakes were detected, and had to be corrected in the

corresponding document(s). This results in new versions, maybe new dates, and as

well a new cover letter.

The cover letter should also contain of the confirmation that electronic and paper

version of all submitted documents are identical.



The following details should be mentioned in the cover letter:

• Name and address of the sponsor

• Name and address of the legal representative, if applicable

• Name and address(es) of the trial site(s) with the names of the principal

investigator(s) and all subinvestigators

• Name and address of the coordinating investigator (in case of a multi-centre

trial)

• Addresses of all involved CROs and Laboratories

• List of all submitted documents with version and date

• Useful information to clarify possibly ambiguous issues, e.g. additional

information to the subject’s insurance

The German template of a cover letter to the EC will be provided in Annex 1.

Confirmation of EudraCT Number

The confirmation e-mail of EudraCT must be submitted together with the application. If

you have applied for the EudraCT number yourself, you should have saved this e-

mail; otherwise, the respective person who did this application should forward it prior

to the submission.

Checklist

The EC Working Group has provided another document, which is called “Checkliste:

Erforderliche Antragsunterlagen für Studien nach AMG” (Checklist: Requested

application documents according to German Drug Law). This document corresponds

to attachment 1 of the detailed guidance for the submission to CAs in the European

Union, revision 2 [6] (now replaced by revision 3 of March 2010) [7], where the

required information for applications to ECs and CAs, sorted by Member States, are

listed. It is also a reflection of § 7 German GCP Ordinance [41], where all required

application documents and requirements are listed.



Section J, the “Check list of information”, will be found in the main menu of the

EudraCT application page. It reflects the checklist of the German EC Working Group

in several issues, although this checklist amplifies many of the sub-items of Section J.

For example, paragraph 3.4 of Section J only asks for an “Ethical assessment made

by the principal/coordinating investigator, if not given in the application form or

protocol” but in the checklist, there are several sub-items to this question. For

example, information should be provided regarding the justification of gender

distribution, inclusion of minors or incapable participants, hindering from participation

in other trials, criteria for premature termination of the trial, that may be regarded as

part of the overall ethical assessment of the trial. For all of these sub-items, instead of

providing separate documents or statements, a reference to the associated

documents may be possible – this will have to be discussed with the EC in charge for

that application. Otherwise, there would be a repetition of details already provided in

module 2, in the protocol, or in the German summary.

The German template of a partly completed checklist for application documents will be

provided in Annex 2, whereas the current template of Section J can be found in Annex

3.

CTA form

In our experience, the CTA form is of detailed interest only for BfArM because we

never had any comments to this document from the EC. In the EC guidance document

it is only mentioned as to give “an easy overview of the trial design and an evaluation

of the expertise needed for the review” [8], but no word that it should be reviewed

itself. Therefore, I will describe the content in the respective chapter for applications to

BfArM. The versions for EC and BfArM only differ slightly. When printing the pdf file for

the EC, the BfArM address and the submission status to BfArM will be shown in

section H.2.1, whereas in section C.2 the contact details of the applicant to the EC will

be given. On the first and last page, the Ethics Committee will be stated as addressee

of the submission. When printing the pdf file for BfArM, it is just the other way round.

Nevertheless, this version must be signed and dated by the applicant, and sent to the

EC as pdf file and xml file as well. Our EC told me once that they use the xml file to



copy out some passages (e.g. the title) for their own documents, maybe an answering

letter or lastly the (positive) opinion. Normally, no word file will be sent to the EC, but

only pdf files, so the possibility to copy the title is otherwise rather limited.

Module 2

Module 2 represents an optional application form for national or local Ethics

Committees, which is requested by our EC on a regular basis. An English template of

this module is given in attachment 4 of the EC guidance document [8], but for

Germany the use of a German version will of course be required.

The required information ranges from EudraCT number and title, to giving the reason

in case of including specific subject groups (e.g. minors), description of the recruitment

procedure, risk assessment, data protection, through to sources of funding, and

financial disclosure information of the investigators. Overall, this document represents

an overview about all issues that will be assessed by the EC in particular when

reviewing the submitted documents.

The EC Working Group has provided a template, which may be used. It is helpful to

create a template for your organisation, and already insert applicable iterative text,

e.g. the description of the recruitment procedure or procedures used to protect the

privacy of recorded data. Therefore, only little information will have to be inserted in

connection with the recent trial, and the document may be finished rather soon after

finalisation of the reference documents. Since the date of signing module 2 will have

to be entered in the checklist, module 2 must be finalised prior to the checklist.

We have agreed upon with our EC to just refer to other documents in the submission

package in order to avoid a superfluous overload of the submitted documentation, if

the information required in module 2 would only be a repetition of details provided

elsewhere, for example the protocol or the German summary.

The German template of a partly completed module 2 to the EC will be provided in

Annex 4, and the blank English template of this module will be attached in Annex 5.



Protocol

The protocol of the clinical trial is one of the most important, if not the most important

document in connection with the conduct of a clinical trial. According to ICH GCP, it is

“a document that describes the objective(s), design, methodology, statistical

considerations, and organisation of a trial. The protocol usually also gives the

background and rationale for the trial, but these could be provided in other protocol

referenced documents.” [27]

Usually, writing or reviewing of a clinical trial protocol does not count within the

responsibility of a regulatory affairs department. Nevertheless, sometimes you may be

asked to check the protocol regarding ethical questions or other aspects, falling

slightly within this area (e.g. insurance, SUSAR reporting), and therefore it is helpful to

know about the requirements. A full-service CRO should have sophisticated personnel

to write complete protocols if requested, or at least to provide adequate assistance,

especially for less experienced pharmaceutical companies.

For clinical trials with diabetic patients or in the field of diabetes, respectively, which is

our main area of operation, the Guideline on clinical investigation of medicinal

products in the treatment of diabetes mellitus [24] should be considered. For other

fields of interest, the respective guidelines should be looked up at appropriate

sources, e.g. the European Medicines Agency.

In general, you will have to think about these issues when writing a clinical trial

protocol:

• What is the planned experimental intervention?

• Have there been any previous trials? What were the results?

• What are the toxicities and side effects of the IMP, if any?

• Will there be any control groups? What is their treatment, if any?

• How will the trial be performed, e.g. number of visits, treatments, drug

application?

• How will the monitoring be planned?



• What are treatment options for the participants or will they receive the study

drug furthermore after the trial has ended?

• Are there any long-term follow-ups?

• Who will be responsible for what?

Resulting from these considerations, these main issues will have to be addressed in

the protocol according to ICH GCP:

• General information

- Title of the trial, protocol identifying number, version, and date

- Contact details of all relevant persons/parties in charge

• Background information

• Detailed information to the IMP such as

- Name and description

- Summary of previous non-clinical and clinical trials

- Risk-benefit assessment

- Description of the dosage, route of administration, and treatment periods

• Description of the trial population

• Trial objective(s) and purpose

• Trial design

- Statement of endpoint(s)

- Description of trial design/type (information e.g. to blinding, control, etc.)

with an overview of procedures and stages

- Description of treatments and dosage (including dosage form, packaging,

and labelling)

- Description of sequences and their duration, including overall duration

- Discontinuation rules

- Accountability procedures for IMP(s) and placebo(s)

- Procedures for randomisation



- Identification of source data

• Selection and withdrawal criteria

- Inclusion, exclusion, and withdrawal criteria

• Treatments

- IMP(s) with name, dosing, route of administration, treatment schedule

- Non-permitted and permitted medication (including rescue medication) or

treatments

- Monitoring of compliance

• Assessment of efficacy and safety

- Specification of parameters

- Methods and timing of assessment, recording, and analysis

- Follow-up of adverse events

• Statistics

- Description of statistical methods including procedures for reporting of

deviations

- Number of participants in each trial site

- Level of significance

- Criteria for termination of the trial

- Accounting of missing or unused data

- Selection of participants included in statistical analysis

• Access to source data/documents

• Quality control and assurance

• Ethical considerations

• Data handling and record keeping

• Financing and insurance (may be provided in separate documents)

• Publication policy (may be provided in a separate document, e.g. the contract)

• References



After finalisation of the protocol, all other documents basing on the protocol can be

issued, e.g. the PIS/PIC, and the case report forms. The regulatory affairs department

should take care for obtaining the signatures of both principal/coordinating investigator

and representative of the sponsor. Without these protocol agreements, the application

would be regarded as formal incomplete. If there are any attachments mentioned in

the protocol, such as an internal approval form of the sponsor, or a list of relevant

departments, those should be submitted as well.

German Summary

The German summary of the protocol must be provided to the EC, if the protocol is

written in English. There are no formal requirements in place for the summary in the

national language. Of main importance is the comprehensibility for the lay reviewers in

the Committee, such as lawyers.

In general, the summary should follow these main headlines, which are basically

consistent with the World Health Organization (WHO) trial registration data set [44]:

• Public title (lay title)

• Health condition(s) to be studied

• Description of intervention(s) and control treatment

• Primary outcome

• Key secondary outcome/s

• Key inclusion and exclusion criteria

• Trial type

• Purpose of the trial

• Allocation to intervention

• Blinding status

• Control group (placebo or active treatment)

• Assignment (parallel, cross-over, cluster, other)



• Anticipated start date and duration

• Target sample size

In the course of the last years, we have developed a template (see Annex 6), which is

sufficient for the review of the EC, and gives a brief overview for all members of our

teams, but it is not regarded as essential document (such as protocol or PIS/PIC) for

the conduct of the trial. Our purpose was as well, to follow the issues of module 2 and

the checklist of the EC working group, which facilitates the referencing to the German

summary. Some information out of this document will be used for the cover letter to

BfArM, because these details, among others, should be provided according to § 7

GCP Ordinance [41].

These are:

• Information on special features of the clinical trial

• Plan for further treatment and medical care of participants after the end of the

trial

• Justification for the gender distribution

Participant Information Sheet / Informed Consent Form

One of the main documents, or in our experience, the main document for the review of

the EC is the participant information sheet (PIS) with detailed information for the trial

participants, and the declaration of consent – either as separate document (PIC) or as

part of the PIS.

The Working Group of the Ethics Committees in Germany has provided a template on

its website (see Annex 7a), which covers all relevant aspects of this document, and

which may be adapted for the specific needs. Sometimes, also a participant diary or a

separate PIS/PIC for an additional voluntary activity (e.g. pharmacogenetic

investigation) shall be used. These documents must also be reviewed by the EC prior

to usage.



A constant update of the PIS/PIC helps to insert all relevant changes, which may have

occurred in the past trials and may be of general importance for other trials as well,

and to match all requirements of the EC (see “Deficiencies”, chapter 2.5).

The main issues for the PIS/PIC are:

• Who is the sponsor of the trial?

• Why will this trial be performed? What are the investigational products?

• What are the activities of the trial? What should be considered before

consent?

• What are the risks and benefits?

• Who may / may not participate?

• Will participants be informed about new data affecting their consent?

• Who will decide whether participants should be excluded from the trial?

• What happens to data and material (e.g. blood or tissue samples) of the

participants?

• How will the participants be compensated?

• How will the participants be insured?

• Who may be contacted, e.g. in case of emergency?

• Which data protection measures are in place?

• How will the consent be obtained?

• Signatures (place, date, time, full name) of investigator and participant

Patient Card

To provide the trial participants with all necessary information in case of emergency in

connection with the trial or any required medically intervention apart from the trial, it

will be useful to create a patient card. The participants should carry along their card

during the whole trial. The card should consist of contact details of the sponsor and

the CRO/trial site, should give information to the subject of the trial (e.g. investigation



of medicine for diabetics), and provide a unique identifier for the trial (trial ID, EudraCT

number) to enable participants and/or other persons, e.g. physicians, to contact the

responsible party in case of need.

Material for Recruitment

In module 2, a description of the recruitment procedure should be provided. In

addition, the EC checklist asks for the justification of the inclusion criteria together with

the statistical evaluation, and the recruitment procedures in paragraph 11.

To meet these requirements, any material for recruitment should be submitted (e.g.

advertisement in newspapers). If no external recruitment is planned – this may be the

case with clinical trials in hospitals, when the patients will only be asked orally to

participate – a proposed advertisement should be submitted, nevertheless, to spare

time and money. There may be difficulties to recruit enough patients, so that later on

external recruitment may become necessary. In that case, an amendment would be

mandatory to receive a positive opinion of the EC in charge for the text of the

advertisement.

Investigator’s Brochure

The investigator’s brochure – IB is the document, which provides all relevant

information about the investigational medicinal product and the rationale for

conducting the respective clinical trial to the investigators and other involved

persons/parties. They should be enabled to understand the given objective by getting

precise information, and to relate the key aspects of the protocol with the nature of the

IMP for their own assessment of the risks and benefits of the proposed trial to the

participants.

For already marketed medicinal products, this document may be replaced by the

summary of product characteristics – SmPC, or the national information for health

professionals (in Germany: “Fachinformation”).

The IB will be provided by the sponsor of the trial and, according to chapter 7 of the

ICH-GCP Guideline [27], should consist of the following minimum aspects:



• Title page with sponsor’s name, identity of the IMP(s), edition number, date

• Table of contents (example given in appendix 2 of the ICH-GCP Guideline)

• Summary (significant physical, chemical, pharmaceutical, pharmacological,

toxicological, pharmacokinetic, metabolic, and clinical information)

• Introduction (chemical name; all active ingredients, pharmacological class;

rationale for performing research with the IMP; indication; etc.)

• Physical, chemical, and pharmaceutical properties and formulation (including

chemical and/or structural formula; instructions for the storage and handling of

the dosage form; etc.)

• Performed nonclinical studies with discussion of the findings (including studies

to potential therapeutic activity and safety)

• Effects in humans (information on pharmacokinetics, metabolism,

pharmacodynamics, dose response, safety, efficacy, and other

pharmacological activities; summaries of any completed clinical trials; etc.)

• Summary of data and guidance for the investigator (with overall discussion of

the nonclinical and clinical data, and summary on different aspects of the

investigational product)

Confirmations of Investigators

In all clinical trials, the principal investigator (and/or the sub-investigators, if any) must

give several confirmations (e.g. financial disclosure statement). In order to provide the

relevant information in one document we have created a template called

Erklärungen/Bestätigungen der Prüfer (Confirmations of investigators) to cover all

those aspects.

For our EC it will not be sufficient to have these confirmations given only by the

principal investigator, but all investigators must sign them. The header states the title,

the protocol ID, and the EudraCT number to assign the document clearly to the

respective trial.



Sometimes, e.g. in case of holidays or illnesses, it may be difficult to obtain all

signatures. Nevertheless, these statements will be required prior to submission of the

application. Therefore, it is of great importance to issue these documents as soon as

possible, and to hand them over to all investigators concerned.

According to the German GCP Ordinance [41] and German Drug Law [22] information

must be given concerning:

• Information of each investigator about previous pharmacological-toxicological

findings and the foreseeable risks of the clinical trial

• Adherence of investigators to data protection principles

• Informing of participants about disclosure of data in connection with § 12 and

13 German GCP Ordinance [41]

• Inclusion of participants relative to the sponsor or to the investigator

• Financial disclosure information of investigators

To follow these requirements easily, each investigator should confirm that

• he/she will read the protocol, the IB and/or SmPC to be informed about the

pharmacological and toxicological data of the IMP and any possible risk for the

participants, and all other relevant documents prior to any trial activities

• he/she will protect personal data of trial participants by using pseudonyms and

that he/she will generally adhere to the principles of data protection

• he/she will inform the trial participants about the necessity to the disclosure of

data to the relevant authorities in case of adverse events, and that

participation in the trial will not be possible if consent in this respect cannot be

obtained

• he/she will not include participants relative to the sponsor or to him-/herself

• he/she does not have any financial of other interest in connection with the

IMP(s)

A German template of a suitable confirmation form is provided in Annex 8.



CVs/GCP Certificates

According to §7(3)6 GCP Ordinance [41], a current CV of all investigators must be

submitted with the application. It may be in the responsibility of a RAM to remind the

investigators to update their CVs as appropriate, and to attend regular GCP trainings,

as this may be required as well by the EC (as it is with the EC of the Medical

Association North Rhine). In our institute we have a personnel database for all

relevant trainings with alerts at a given time to renew the trainings. For example, for

GCP trainings, the period for renewal is 22-28 months.

It will be possible to include investigators who are not physicians according to § 7(2)6

GCP Ordinance [41], but their participation should be justified thoroughly by describing

the respective activities in the trial, and the relevant professional qualification must be

provided.

Authorisation Letter

If not the sponsor but an authorized party, such as a CRO, will be responsible for the

application, an authorisation letter of the sponsor will be required. A template of such

an authorisation letter may be provided to the sponsor to facilitate the execution.

The template of an authorisation letter is provided in Annex 9.

If the sponsor is not situated in an EU Member State, it may be useful to provide a

responsibility letter of the legal representative within the EU as well. This letter should

confirm, that the representative will take over all legal responsibilities for the conduct

of the trial within the EU.

Contract

One of the requirements of the EC according to § 7(3)16 GCP Ordinance [41] is the

proposed contract between the sponsor and the trial site. The main topics should be

addressed, and the financing of the trial must be assured, although the document

would not have to be final and signed prior to submission. Additionally, there is no

need to reveal the budget to the EC.



One part of the agreement should be a responsibility split list to identify clearly the

duties of each concerned party. The other part will be the work order for the specific

trial, which could be rather short, if there is a master service agreement in place. The

master service agreement is a contract that covers more than one trial, and will be

useful, if there are repeated trials with the same sponsor.

Insurances

According to § 7(3)13 GCP Ordinance [41] in connection with § 40 (1)8 and (3) AMG

[22], an insurance of the trial participants covering at least 500,000 EUR must be in

place for cases of injury or death in connection with clinical trials. The insurance

company must be based in the EU or another country of the European Economic

Area. Whereas, in contrast to the statement in section 4.8 of the detailed guidance for

applications to ECs: “Also the insurance or indemnity arrangements to cover the

liability of the sponsor and investigator should be stated” [8], we were never asked for

the insurance documents regarding liability of sponsor or investigator.

The confirmation or insurance policy, and other documents designated to be given to

the participants, should be in German – otherwise the insured person would not be

able to follow the requirements in case that an insured event occurs.

There are two subsets of possible insurances for the participants:

• Subject’s Insurance

This insurance is a mandatory document of the application package to the EC. It is of

great importance to provide not only the specific confirmation of the insurance

company, but also all other documents referred to in this confirmation. These are

mainly the “General Conditions of Insurance” and any other listed documents, such as

written or additional conditions. Those need not in any case be given to the trial

participants, but must be reviewed by the EC, though.

The background for this requirement is the possibility of preclusive conditions in the

additional documents concerning the trial participants or the proposed trial activities.

For example, according to the written conditions participants of a certain age would be



excluded from the insurance, whereas pursuant to the protocol those age groups may

be included.

It is within the responsibility of the RAM to check the insurance documents accordingly

– also regarding the compliance of the versions mentioned in the confirmation and

provided by the insurance company. For example, if the confirmation refers to

“General Conditions” that belong to a yearly insurance contract, this version must be

attached and not a version that belongs to a project contract (insurance only for this

very trial).

A specific requirement of an EC (as for the EC of the Medical Association North

Rhine) may be the following confirmation:

“The insurer confirms that the insurance itself continues to be valid even if the

authorities recall their approval for the specific trial or put it on hold, if the site has

proceeded with the conduction due to the lack of knowledge about this decision.

Based on § 42a(4) AMG [22] the clinical trial has to be stopped immediately, if the

authorities recall their approval for the specific trial or put it on hold".

If you know about these or any other specific requirements, it will be of great help for

the study team and the sponsor to make them aware of the missing documents or

statements in order to avoid deficiency letters. Some sponsors may stick to their

decision not to provide some documents or not to include the statement mentioned

above, though, but they should at least be informed about the possibility of receiving a

respective deficiency letter.

It is also recommendable to give some information about the duration of the insurance

in the cover letter. Very often the general conditions of the insurance state: “The

insurance is valid for adverse health effects from all clinical trials that have begun

during the effectiveness of the insurance policy, regardless, if the insurance contract

had already ended at the time of the insured event.” The reference to this (or any

equal) statement in the submitted insurance documents is given in any of our cover

letters to avoid inquiries from the EC.



• Accident Insurance

The EC Working Group recommends an accident insurance for all trial participants.

This insurance should cover any accident on their way to the trial site(s) or on its

grounds.

Depending on the members of the Ethics Committee in charge, it may be possible that

they require a respective statement in the PIS, if no accident insurance was

concluded. Furthermore, some members of the EC require a specific amount of the

insurance, preferably also 500,000 EUR as with the subject’s insurance. Due to the

fact that the accident insurance is just a recommendation of the EC working group,

and there is an ongoing discussion about the necessity among the ECs, by now this

request does not need to be implemented, and it is up to the sponsor to decide

whether this insurance should be in place or not.

Eligibility of the Trial Site

One topic of the EC review is the eligibility of the investigational site for the conduct of

the proposed trial. The EC would like to prove that devices, equipment, and the

personnel are adequate for the planned purpose. Previous experience with similar

trials should be mentioned as well.

In our case, we send a complete overview of the local conditions to the responsible

EC once a year (and any subsequent update of these conditions) to document the

suitability of our institute to perform clinical trials with medicinal products or medical

devices mainly in the field of diabetes. The EC returns a confirmation that they have

approved the documentation, and that we may refer to that confirmation in the

upcoming trials.

Case Report Forms

Some times before, the EC asked for draft versions of the case report forms. Since

neither the GCP Ordinance [41] nor the German Drug Law [22] require a review of

these forms, we have decided to oppose to this request. One reason is the fact that

these forms normally are in a very early draft status at the point of application, and the



other reason is the frequent use of electronic CRFs. That would make it really difficult

to provide a paper version for review.

2.4.2 BfArM

Cover Letter

The cover letter for BfArM is similar to this to the EC, and here it is also an effective

means to provide essential or additional information, which the reviewing assessors

may otherwise hardly detect in the application documents.

In the cover letter to BfArM you will also have to confirm that electronic and paper

version of all submitted documents are identical.

The following details should be mentioned in the BfArM cover letter:

• Name and address of the sponsor

• Name and address of the legal representative, if applicable

• Name(s) and address(es) of the trial site(s) with the name(s) of the principal

investigator(s)

• Name and address of the coordinating investigator (in case of a multi-centre

trial)

• Addresses of all involved CROs and laboratories

• Address of the responsible Ethics Committee and, if applicable, of the

competent authority(ies) of other MS

• Indications of particularities of the clinical trial and references to the sources of

the respective information in the presented documents (for example first-time

administration of the active substance to humans, administration to a special

population of test subjects or patients, etc.)

• Plan for the further treatment and medical supervision of the affected persons

after the end of the clinical trial according to § 7(2)13 GCP-V [41]

• Justification for the gender distribution of the group of affected persons

according to § 7(2)12 GCP-V [41]



• Confirmation according to § 7(2)15 GCP-V [41] that the participants shall be

informed of the dissemination of their pseudonymous data with the explanation

that affected persons not consenting to the dissemination of information

cannot be included in the clinical trial

• Confirmation according to § 5(2)2 GCP-V [41] that the telephone numbers of

the sponsor and the CRO will be listed in accompanying documents (e.g.

participant card and/or PIS/PIC), if not provided on the labels

• Confirmation according to § 5(2)11 GCP-V [41] that the EudraCT will be listed

in accompanying documents (e.g. participant card and/or PIS/PIC), if not

provided on the labels

• Confirmation according to § 5(2)10 GCP-V [41] that the protocol code will be

listed in accompanying documents (e.g. participant card and/or PIS/PIC), if not

provided on the labels

• Confirmation according to § 7(2)6 GCP-V [41] that only medical doctors are

acting as investigators in the clinical trial or justification for involvement of non-

medical investigators, respectively

• List of all submitted documents with version and date

• Useful information to clarify possibly ambiguous issues, e.g. additional

information to the manufacturing licences or explanatory notes to clinical trials

conducted with the same IMP

A German template of a cover letter to BfArM is provided in Annex 10.

CTA Form

The clinical trial authorisation application form is the Annex 1 of EudraLex – Volume

10 Clinical trials guidelines [20] and will be provided by EudraCT, the clinical trials

database of the European Union. EudraCT is the platform for sponsors or authorized

applicants to obtain the unique EudraCT number, which clearly identifies the clinical

trial, and to fill out the application form, save it as xml file and print a pdf version for

submission to Ethics Committee(s) and competent authority(ies).



Detailed guidance for the completion of this document is given in the EudraCT V7.0

User Manual [16], so in the following I will just give an overview.

To get a EudraCT number, the first step of the application process on EudraCT, you

will have to go to the EudraCT homepage (https://eudract.ema.europa.eu/) and

choose “Access to EudraCT v7 Application”.

On this welcome page, you have several options:

• EudraCT Number Step 1: Apply for Security Code

• EudraCT Number Step 2: Apply for EudraCT Number

• Create New Clinical Trial Application: Click here to create a new Clinical Trial

Application

• Load Saved Clinical Trial Application: Click here to load a saved Clinical Trial

Application

• Download CT Amendment Form: Download CT Amendment Form

• Download CT End of Trial Form: Download CT End of Trial Form

• Return to EudraCT Home Page: Return to EudraCT Home Page

https://eudract.ema.europa.eu/

https://eudract.ema.europa.eu/eudract/securityCheck.do?method=read

https://eudract.ema.europa.eu/eudract/eudractNumber.do?method=read

https://eudract.ema.europa.eu/eudract/ctApplication.do?method=createNew

https://eudract.ema.europa.eu/eudract/ctApplication.do?method=createNew

https://eudract.ema.europa.eu/eudract/uploadXML.do?method=read

https://eudract.ema.europa.eu/eudract/uploadXML.do?method=read

http://ec.europa.eu/health/documents/eudralex/vol-10/index_en.htm


https://eudract.ema.europa.eu/eudract/redirectToExternalURL.do?urlId=homeURLPublic



Below, a screenshot of this welcome page is shown:

Figure 5: Welcome Page; EudraCT (Public Site); accessed on 15 December 2010



As first step “Apply for Security Code” should be chosen – on the next page (as shown

in the screenshot below) you will only have to enter your name and e-mail address to

which a security code will be sent that is valid 24 hours.

Figure 6: Get Security Code; EudraCT (Public Site); accessed on 15 December 2010

This code will be used for the “Get EudraCT Number” page, where in addition to the

code some basic information will have to be inserted:

• Requestor name

• Requestor's organisation name, with town/city and country

• Sponsor's protocol code number

• E-mail address to which the EudraCT number shall be sent

• Determination, if the trial is connected with a Paediatric Investigation Plan

(PIP)

• Determination, if there are third countries where the trial will be conducted

• Member States where the trial will be conducted

After completing this page, the EudraCT number will shortly be sent to the given e-

mail address. Since this confirmation e-mail will be part of the submission package in

several MS, it should be saved to the respective file.



Below, a screenshot of the “Get EudraCT Number” page is shown:

Figure 7: Get EudraCt Number; EudraCT (Public Site); accessed on 15 December 2010



The next step is the creation of a new clinical trial application. When clicking on the

respective link you will be asked to choose the responsible MS competent authority

(only Germany has two of them, BfArM and PEI), and to enter the EudraCT number as

you can see below:

Figure 8: Initial Required Information; EudraCT (Public Site); accessed on 15 December 2010

On the next pages, all details of the clinical trial, belonging to the following sections,

will be asked:

A: Trial identification – for title, protocol code, version, date, and if it is a

resubmission.

B: Sponsor identification – for the sponsor organisation and contact details. In case

of a sponsor outside the EU, a legal representative must be designated and the

information must be given by clicking on “add legal representative”. In addition, you

will have to decide whether the status of the sponsor is commercial or non-

commercial. Non-commercial sponsors are e.g. universities.

C: Applicant identification – for details of the applicants to either the competent

authority or the Ethics Committee. The responsible person may be the same or

different, and it may be the sponsor or an authorised person or organisation.

D: Information on the IMPs – for details to the investigational medicinal product(s) in

this trial, as either test IMP(s) or comparator(s). If different strengths of an IMP will be

investigated in the clinical trial, any strength should be regarded as separate IMP.



If the IMP has a manufacturing authorisation (MA), the name of the MA holder must be

inserted together with trade name and MA number, which can be found in the

summary of product characteristics – SmPC. If the IMP is modified in relation to its

MA, the kind of modification must be mentioned, e.g. encapsulated. As dossier for

products with a MA in a MS or ICH country the SmPC is sufficient, whereas for new

products a full dossier must be submitted. For known products with some changes, or

when a cross-reference to the application details of another applicant is authorised, a

simplified dossier may be possible. For the decision whether a simplified IMPD may

be used, the guidance document for the request to the competent authorities [7] gives

detailed information in its Table 1.

If the IMP was already authorised previously, this information must be given as well as

the decision whether the IMP had been the subject of scientific advice(s). In this case,

a summary of the advice(s) should be provided with the submitted documents.

The pharmaceutical form and the route of administration must be chosen from drop-

down lists, and the maximum duration of treatment of a subject with the maximal

allowed dose must be given.

The next screens refer to the type of IMP, whether it is of chemical or biological origin,

a cell therapy product, gene therapy product, radiopharmaceutical therapy product, or

any other medicinal product.

With the link “add active substance”, the information about the active substance (AS)

as part of the IMP and its concentration (unit, type and number) should be provided in

a new window. If there is more than one AS in the IMP (combination products), all of

them will have to be listed.

If there are several similar IMPs with only different concentrations of the active

substance, they will have to be listed with an own section for each concentration. This

may be done easily be copying the complete section and just changing the

concentration units.

Non-IMPs such as challenge agents, concomitant medication, or rescue medication

should not be listed in this section. For the decision whether a medicinal product in a

trial will be regarded as IMP or non-IMP, EudraLex, Volume 10 – Clinical trials



guidelines Chapter V, Additional Information: Guidance on Investigational Medicinal

Products (IMPs) and other Medicinal Products used in Clinical Trials [23], should be

consulted. Currently, this guidance document will be found in EudraLex, Volume 10 –

Clinical trials guidelines, Chapter III: Quality of the Investigational Medicinal Product.

[20]

D.7. Information on the placebos – for the question, if there are placebos to be

used. In case of answering “yes”, some information must be given after clicking on

“add placebo”. Not only pharmaceutical form and route of administration must be

provided, but also the information for which of the IMPs it is the placebo. If the placebo

is not otherwise identical, except the lack of active substance, the major ingredients

must be listed. Possibly, in case the placebo is not otherwise identical, an adequate

dossier about its quality will have to be provided as well.

D.8. Site(s) where the qualified person certifies batch release – for the

determination, who will be responsible for the final QP release of the IMPs before

distribution to the investigational site(s) and/or the investigator(s). Only the final

release of a QP (qualified person) will have to be documented, but for all

manufacturing sites a valid manufacturing authorisation (alternatively a GMP

certificate) must be submitted.

D.8.1 may be chosen for all IMPs that

• have a MA in the EU and

• are sourced from the EU market and

• are used in the trial without modification (e.g. not encapsulated) and

• are packed and labelled for local use only as per article 9.2 of the Directive

2005/28/EC [4]. In this article it is described, that a reconstitution prior to use

or packaging by pharmacists or other authorized persons does not require

authorisation, if these handlings are carried out in hospitals, health centres or

clinics. However, this is only valid, if the IMP will be used solely in this

institution.



For all other products and/or trial sites, respectively, a releasing site will have to be

mentioned in section D.8.2 (as manufacturer, importer or both) by providing the

manufacturing number.

E. General information on the trial – for the medical conditions and the classification

code [to be looked up at MedDRA, a registered trademark of the International

Federation of Pharmaceutical Manufacturers and Associations (IFPMA)]. The main

and the secondary objective(s) as well as the endpoint(s) should be listed. For the in-

and exclusion criteria only the most important should be listed – on the one hand

because only 5,000 characters can be inserted into the text field, on the other hand

because any change to criteria that are listed here (in case of an amendment to the

protocol), even if not important, will lead to the need of submitting a new application

form to BfArM. For the decision, what the main criteria for the respective trial are, the

principal investigator or any other responsible person may be asked. For the

completion of the CTA form (and as well for the preparation of the German summary

of the protocol), it would be helpful to decide on key in- and exclusion criteria while

writing the protocol. They could be listed in the protocol synopsis, which is normally

provided at the beginning of the document, and then copied into the application form

without further request, which of the (sometimes more than 30 in- and/or exclusion

criteria) are the most important.

The scope, type, and phase of the trial must be determined as well as the trial design

(e.g. double-blind, randomised). If it is controlled, the type of comparator (placebo or

other medicinal product) should be chosen, and the definition of the end of the trial

should be provided.

Finally, yet importantly, the number of sites, the involvement of countries outside the

EU, and the duration of the trial both in the concerned MS, and in all countries in case

of multi-centre trials are inquired here.

F. Population of trial subjects – for any details of the trial participants, beginning

with the age span, gender, the question whether the trial subjects are patients or

healthy participants, and if vulnerable persons (e.g. pregnant or nursing women) are

involved. Furthermore, the proposed number of trial participants should be given, and

any special plan for treatment after the trial has ended.

http://www.ifpma.org/



G. Clinical trial sites/investigators in the member state concerned by this request – for the contact details of the principle investigator (in case of a multi-centre

trial the coordinating investigator, and the principle investigators of all trial sites)

should be given.

In the next subsections, the central technical facilities (providing services for all or

most of the trial sites), and those concerned with the measurement of the main

evaluation criteria must be listed, whereas local labs need not to be named

(nevertheless, we had a BfArM query for one trial where not all local laboratories were

listed). For these facilities the subcontracted duties will have to be stated – sometimes

the information will be given in the protocol, but the contract or responsibility split list

may also be a source for this information. Not only facilities in the concerned MS will

have to be named, but also those in third countries, even if not situated in the EU.

Any other duties, such as CRO activities, data management, monitoring, or medical

writing will have to be listed with the respective organisation in charge.

H. Competent authority / ethics committee in the member state concerned by this request – for the address of the involved CA and EC, the date of submission, and

the authorisation status. For the submission to EC, the details of the CA will have to

be given and vice versa.

I. Signature of the applicant in the member state – for the confirmation (on behalf

of the sponsor in case of application through an authorised party) that the information

in the application form is correct, that the trial will be conducted according to

applicable principles, that it is reasonable to perform the trial, that SUSARs and safety

reports will be submitted according to legal bases, and that the synopsis of the trial

report will be submitted in due time.



Below, a screenshot of a main menu page with the possible options is shown:

Figure 9: Main Menu Page; EudraCT (Public Site); accessed on 15 December 2010

Important information to the completion of the form:

With “edit” missing information can be added or inserted details can be corrected –

with “delete” the content will be deleted immediately without any further request (take

care!).

The system has 'timeout' after 30 minutes of inactivity. To avoid the loss of data, the

application form must be saved to the own computer or any other accessible drive by

clicking on “Save as XML”, which should be repeated regularly in the course of

completing the form. In the EudraCT system, only the data of the current session will

be saved. The name of the file will be FullData.xml as given by EudraCT – it is useful



to rename the file associated to the respective trial. Otherwise it could happen, that an

already saved xml file would be replaced accidentally – which means the loss of the

complete data of the formerly completed application form.

Once you have ended to complete the form and closed the file, you may open it again

by choosing “Load Saved Clinical Trial Application” which will lead you to the following

page, where you can browse your files and upload the required xml file:

Figure 10: Load Application from File; EudraCT (Public Site); accessed on 15 December 2010

A click on “Next” in a multi-sided section will bring you to the next page; with “Cancel”

you will either return to the first page of that section or to the main menu, depending

on the section, without saving any changes. The last page of each section has the

options “Continue” to return to the main menu and “Cancel” to close this section

without any entries or changes. A click on “Application Menu Page” will always lead to

the main menu.

In most sections, each tick box must be ticked, mostly “yes” or “no”. This is a new

option in this current version 7.0 (the tick fields in the former version could be left open

without any validation failures), and shall probably make sure that no decision will be

just forgotten. Nevertheless, in some sections, this is no logical procedure. For

example in section F.1 Age span: If you have ticked “no” to F.1.1 “Less than 18 years”

you will have to answer all questions F.1.1.1 to F.1.1.6, although the instruction says,

“If yes, specify”. Otherwise, the validation report will list these missing ticks of “no” as

mistakes. The concrete wording in the validation report is: “If F.1.1 is "Yes" all sub-

questions should be answered and at least one of F.1.1.1 to F.1.1.6 should be "Yes".



If F.1.1 is "No" then sub-questions F.1.1.1 to F.1.1.6 should be all answered "No".” But

if you try to complete the form as requested, you will always get the same comment. In

contrast, if you tick all sub-questions with “no”, regardless of the instruction, this

section will be regarded as correct. This is also the fact in some other sections, so the

next version of the EudraCT application form will hopefully be revised concerning

these inconsistencies.

Sometimes, a text field may be left open, e.g. if question E.8.2.3 “If controlled specify

the comparator – Other” is ticked “no”, no answer should be given in the field below. In

contrast, the text field to question E.8.8 “Definition of the end of trial” should be at least

filled with “n/a”, otherwise the validation report will list a mistake in that section. These

fields are called “mandatory” and must at least be filled with “n/a” or “not applicable”.

The above-mentioned validation report can be created by clicking on “Validate XML” in

the main menu.

Below, a screenshot of the first section of a validation report with deficiencies is

shown:

Figure 11: Validate Application Results with Failures; EudraCT (Public Site); accessed on 27 December 2010



As an example, the failures in section E. “General Information on the Trial” are shown

below:

Figure 12: Failures in Section E; EudraCT (Public Site); accessed on 27 December 2010



For a completed application form without any more failures, you will get a validation

report as shown below:

Figure 13: Validate Application Results without Failures; EudraCT (Public Site); accessed on 28 December 2010

All validation rules may be found on the EudraCT website in the file “EudraCT

Validation Rules” [17].

When all failures have been solved and the application form is ready for submission,

the link “Prepare Submission Package” on the main menu page should be chosen – a

complete set of documents for either BfArM or EC submission will be prepared which

contains of the pdf file, xml file, and the validation report in a zip file.

Investigational Medicinal Product Dossier – IMPD

The most important part of the application documents to BfArM, apart from the

protocol, is the dossier of the investigational product in the proposed trial. In Directive

2001/20/EC, Article 2(d), IMPs are defined as “a pharmaceutical form of an active

substance or placebo being tested or used as a reference in a clinical trial, including

products already with a marketing authorisation but used or assembled (formulated or

packaged) in a way different from the authorised form, or when used for an

unauthorised indication, or when used to gain further information about the authorised

form.” [11]



Given this definition, reference products used as comparators should also be

considered as IMPs, which includes placebos as well (but only quality data will be

required here).

The sponsor should always provide this documentation, and normally no review from

our side will be required. Nevertheless, if the principal investigator has profound

knowledge of the IMP(s), he/she may be asked to review certain sections in the

documents, and to give his/her input, if possible.

If the use of the IMP had already been approved for a previously submitted clinical trial

with the same sponsor, and no alterations were made, a full reference to that

documentation will be possible. If there are further results to this IMP, which were not

subject of the previous application, a simplified IMPD with reference to the identical

documents may be submitted by clearly demonstrating all new data.

In EudraLex – Volume 10, Chapter II: “Monitoring and Pharmacovigilance” the

“Guideline on the requirements to the chemical and pharmaceutical quality

documentation concerning investigational medicinal products in clinical trials” [25]

gives detailed information on the requirements of the documentation in an IMP dossier

to be submitted in a clinical trial application. Consequently, just a brief overview should

be given here. Whenever appropriate, the applicant should provide the information in

the CTD (Common Technical Document) format as given in EudraLex – Volume 2B,

“Presentation and content of the dossier” [18], which facilitates the implementation of

further knowledge into the required format for the application for marketing

authorisation.

The aim of the details given in the IMPD is only for application purposes regarding a

proposed clinical trial. Therefore, there is no need to provide the same amount of

information as for an application for marketing authorisation. Sufficient information

about the drug supplies used in the trial, and about the safety for the included trial

participants should be given, and the content should be regarded in connection with

the trial protocol, and other associated documents, such as the IB.

The table of contents should contain of data to quality, manufacture, and control of the

IMP, non-clinical pharmacology and toxicology data, data of previous clinical trials and



other human experience, an overall risk and benefit assessment, and should

preferably follow these topics in the CTD format:

• Introduction

• Chemical Pharmaceutical Data

- Drug Substance

o General Information

o Manufacture

o Characterisation

o Control of Drug Substance

o Reference Standards or Materials

o Container Closure System

o Stability

- Medicinal Product

o Description and Composition of the Medicinal Product

o Pharmaceutical Development

o Manufacture

o Control of Excipients

o Control of Medicinal Product

o Reference Standards or Materials

o Container Closure System

o Stability

• Appendices

- Facilities and Equipment

- Adventitious Agents Safety Evaluation

- Novel Excipients

- Solvents for Reconstitution and Diluents

• Non-Clinical Pharmacology, Pharmacokinetics and Toxicology



- Test Materials used in Toxicity Studies

- Integrated Assessment of the Data Package

- List of Studies Conducted & References

- GLP statement and Bioanalytical Methods

• Clinical Data

- Clinical Pharmacology

- Clinical Pharmacokinetics

- Human Exposure

• Benefits and Risks Assessment

For IMPs of biological origin, a TSE (Transmissible Spongiform Encephalopathy)

certificate, to prove the safety of the trial participants in this regard, may be required

for the application package as well.

Sometimes, the sponsor will also provide SUSAR line listings with the IMP documents.

Labelling

According to § 5 GCP Ordinance [41], a draft version of the proposed labelling for the

IMP(s) must be submitted. The labelling should comply with the principles laid down in

Directive 2003/94/EC [3] and the 3rd Notification of the German competent authorities

[1]. Additionally, Table 1 of the GMP Guideline [19] gives a detailed overview of the

documentation required for the labels of the investigational product(s). The following

aspects must be considered and missing data should be justified:

a) The name, address and telephone number of the sponsor, contract research

organisation or investigator (i.e. the main contact for information on the

product, clinical trial and emergency unblinding)

b) The pharmaceutical dosage form, route of administration, quantity of dosage

units, and in the case of open trials, the name/identifier and strength/potency

c) The batch and/or code number (in German: Chargen-Bezeichnung) to identify

the contents and packaging operation, the abbreviation should be "Ch.-B."



d) A trial reference code and the EudraCT number, allowing identification of the

trial, trial site, investigator and sponsor, if not given elsewhere (e.g. PIS/PIC)

e) The trial participant identification number/treatment number and, where

relevant, the visit number, if not given in an accompanying document

f) The name of the investigator – if not included in a) or d)

g) Directions for use (reference may be made to a leaflet or other explanatory

document intended for the trial participant or person administering the product)

h) The advice “for clinical trial use only” or similar wording

i) The storage conditions, if applicable

j) The period of use [use-by date ("verwendbar bis"), expiry date or re-test date

as applicable], in month/year format and in a manner that avoids any

ambiguity

k) The advice “keep out of reach of children” except when the product is for use

in trials where the product is not taken home by the participants

l) Special precautions for the disposal of unused IMP(s) or other special

precautions to avoid danger to the health of non-affected persons and the

environment, and indications for their return (this is a specific requirement

mentioned in BfArM’s 3rd notification)

As a result, in Germany on both the primary and secondary packaging, sections a) to

l) must be given. An exception will be made for section a) where the address and

telephone number may appear in a leaflet or card, which provides these details, and

the trial participant has been instructed to keep this document with him at all times.

Primary and secondary packaging

a) except telephone number and address

b) - l)

Figure 14: Labeltext “Primary and secondary packaging”



For the primary packaging, where primary and secondary packaging remain together

all the time, and the outer packaging contains of the information of sections a) to l) the

following sections must be printed: a) except address and telephone number, b)

except the route of administration for oral solid dose forms, c), d), and e).

Primary packagingprimary and secondary packaging remain together


b) except the route of administration for oral solid dose forms

c) - e)

Figure 15: Labeltext “Primary packaging if primary / secondary packaging remain together”

If the primary packaging is a blister or small unit, and the outer packaging contains of

the information of sections a) to l), the list may be shortened to a) except address and

telephone number, b) except the route of administration for oral solid dose forms, and

pharmaceutical dosage form, and quantity of dosage units, c), d), and e).

Primary packaging blisters or small units


b) except the route of administration for oral solid dose forms, and pharmaceutical dosage form, and quantity of dosage units

c) - e)

Figure 16: Labeltext “Primary packaging for blisters or small units”

Normally, the labels will be provided by the sponsor, but it is also in the responsibility

of the RAM to check the correctness of the documents regarding the required

information.

As verification that some information will be provided in other documents, the

respective leaflet or participation card should be added to the application package,

and an explanation should be given in the cover letter or an additional document.

A German template of a possible label will be added in Annex 11.



Manufacturing and Import Licences

According to the requirements of the already mentioned directives, guidelines and

ordinances, especially EudraLex – Volume 4, EU Guidelines to Good Manufacturing

Practice, Annex 13 [19], the manufacturing licences of all participating manufacturers,

stating the scope (all processes of manufacturing inclusive dividing up, packaging, and

presentation) and validity of the authorisation, must be provided for the BfArM review

as proof of GMP compliance.

In case of a manufacturer situated outside the ICH region, an import licence and a

certification of GMP compliance by the qualified person responsible for the IMP in the

EU Member State must be submitted. Nevertheless, for some countries a “Mutual

Recognition Agreement” [34] may be in place, so that the manufacturing licence

remains valid and no re-control will be necessary. This is the fact for Australia,

Canada, Switzerland and New Zealand [33].

No GMP documentation is needed for IMPs with a marketing authorisation in the EU

or an ICH country, given that they are not modified (e.g. over-encapsulated).

If you submit more than one manufacturing licence, information in the cover letter

should be added, who of these manufacturers will be responsible for the batch

release. Although this information is already given in the EudraCT application form in

section D.8. “Site(s) where the qualified person certifies batch release”, we had

queries to that question in comparable situations.

2.5 Deficiencies

After receipt of the application, the EC and BfArM have 10 days to check the

documents formally, and to ask for updated documents. As pointed out before, the

applicant has 14 days to correct any formal deficiencies. After a formal complete

submission, there is 30 days time for the review of the submission package.

In general, all requirements mentioned in the GCP Ordinance [41] as mandatory will

cause deficiency letters, if missing. Nevertheless, many issues will only be detected in

the course of various applications and growing experience, because in a single



application (hopefully) only a few mistakes will be made. It is therefore

recommendable to set up a database with past queries of the EC and BfArM, to avoid

repeating the same mistakes.

For all documents required by the EC to answer their deficiency letters, the number of

copies is the same as in the submission package (ninefold). For BfArM the number

depends on the departments, which ask for revised documentation. At least two paper

copies are required (in the case only one department, e.g. quality, has concerns, then

one copy goes to the respective department and the other one to the project manager

in charge), but in no case more than four.

For both EC and BfArM, an additional CD ROM with the files as pdf (and xml, if

changes to the application form occured) must be provided.


Formal Deficiencies

The formal requirements range from the correct number of paper copies, over the

signature pages of both sponsor representative and principal investigator, to the

insurance documents. After receiving a letter of formal deficiency, it will be helpful to

add the query to a checklist to avoid that mistake in the future, which may be just a

clarification for the EC members in the cover letter.

Most of the formal deficiencies are evadable by an accurate preparation of the

submission package, and a final review through a second person. Not only once, we

have detected a missing document in this review, which would otherwise have caused

a deficiency letter.

Possible formal faults would be:

• Missing information in the cover letter according to § 7(2)2 GCP Ordinance

[41]

• Wrong version numbers and dates of documents listed in the cover letter

• Protocol signature pages are missing



• Cover letter, module 2, EC checklist and/or CTA form have not been signed or

only copies of the signature pages are provided (these documents must be

sent with one original signature and the remaining as copies)

• Insurance documents are incomplete, e.g. the “General Insurance Conditions”

(Allgemeine Versicherungsbedingungen) or specific conditions mentioned in

the confirmation of insurance are missing

• CVs, GCP certificates or statements of one or more investigators are missing

• EudraCT number is missing on relevant documents (e.g. protocol, PIS/PIC)

• Responsibility split list is missing in the information about funding of the trial

• CD ROM with the submitted documents as pdf files is missing

Formal deficiencies should be avoided by all means, because the review period will

not begin until the queries have been answered. Nevertheless, sometimes it is not

possible to submit completely, because the EC may have decided to change their

requirements without notifying the applicants beforehand. In this case, the internal

checklist should be amended accordingly to leastwise avoid the “new” requirement in

the future. Unfortunately, we had such a situation in the beginning of 2010, when we

submitted four trials at a time and consequently received four letters of formal

deficiencies to the same issue – that sadly deteriorated our internal statistics on

successful submissions.

Contentual Deficiencies

As to our experience, the contentual deficiencies of the EC refer mainly to the

participant information sheet/informed consent form (PIS/PIC).

Since we mainly deal with clinical trials in the field of diabetes, some of these

deficiencies refer to the specific conditions, and in- and exclusion criteria of diabetic

patients, but they might easily be extrapolated to other medical conditions.



Possible contentual faults of the PIS/PIC could be:

• The wording of the PIS/PIC should be in lay terms – for example the following

terms were classified as too hard to understand:

- orally administered (oral verabreicht)

- menopausal condition (menopausaler Status)

- bronchospasm (Bronchospasmus)

- angioedema (Angioödem)

- coding (codieren)

- genome (Genom)

- reversible (reversibel)

• If medical devices are handed out to the participants (here: glucometers), their

use must be trained through the investigators

• Diaries to be used in the trial, must be explained and demonstrated

• If a trial consists of several groups, each group should be given an own

PIS/PIC (i.e. no information will be given to one group, which is only of interest

for the other)

• The complete address of the sponsor must be provided in the PIS

• In case of taking blood samples, information to the risk must be provided, e.g.

injury of nerves, bruises, infection

• Risks and adverse effects must be explained clearly

• For genetic investigation, a separate PIS/PIC must be created

• The PIS/PIC must be given to foreign participants in their mother tongue

- it will be sufficient to confirm, that the participants will be provided with a

certified translation and that this version is similar to the reviewed and

approved German version

• All documents given to the participants must be reviewed by the EC – e.g. if a

diary is mentioned in the protocol or in the PIS, the EC should receive it



• If participants must stay in bed for a longer period, anti-thrombosis stockings

should be provided, the use of heparin should be considered, and participants

with a history of deep leg thrombosis must be excluded from participation

• Treatment options other than the IMP should only be mentioned in trials with

patients

• Information to data protection should be highlighted (e.g. surrounded by a

frame)

• Insurance sums must be specified

• For information to possible adverse events also the measures for prevention

or treatment should be indicated (e.g. intake of carbohydrates in case of

hypoglycemia)

• The information to the IMP(s) should be adequate (not just briefly)

• For situations of pregnancy during the trial, the procedure for reporting (when,

to whom, how long), and further handling should be defined

• Blood loss amounts in the course of the trial must be stated clearly, and an

advice not to donate blood just before, during, and shortly after the trial should

be included

• Measures of contraception should be defined clearly, also for male participants

with regard to their female partners

For the protocol, deficiencies are rare regarding the EC review. Possible objections

could be:

• Treatment guidelines for the specific medical condition should be regarded

• Publication clause should be in compliance with the Declaration of Helsinki

• Similar information in different sections should be congruent (here: the

definition of hypoglycaemia was not the same in two different sections, in one

section “as judged by the investigator” and in the other a specific definition

was given)



• Inclusion criteria should contain of upper and lower limits (here: HbA1c level in

diabetic patients)

• If the conditions of the trial are challenging (here: frequently changed

treatment and several washout phases), participants should agree to inform

their family doctor about the participation

• Individual withdrawal criteria should be defined decisively – just a reference to

the section “Adverse Events” will not be sufficient

Other critical documents are the insurance confirmation and associated documents.

As already stated in section 2.4.1 “Insurances”, not only the confirmation letters of the

subject (and travel insurance, if applicable), are important, but also the additional

documents, mainly the general conditions of the insurance, stating the overall

responsibilities of the insured person and the insurer. The confirmation should

therefore be reviewed thoroughly before submission, and missing or wrong

information should be requested at the insurer. If relevant documents, information,

and/or confirmations as stated above are missing, the EC will most likely detect that,

and send a respective deficiency letter.

For other documents in the submission package, deficiencies are mostly rare. One

objection could be that the German titles in the documents (e.g. PIS, German

summary, and module 2) are not similar, another one that the in- and exclusion criteria

in the PIS, or the amount of compensation in the advertisement do not correspond to

the protocol.

2.5.2 BfArM

Formal Deficiencies

Possible formal deficiencies in the application to BfArM are in general similar to those

in the package sent to the EC. Because there are some documents, which will only be

sent to BfArM, such as the manufacturing licences or the draft versions of the

proposed labelling, there may be some additional queries. However, in contrast to the

EC, the clerks dealing with the submission at BfArM are often more pragmatic.

Sometimes, they called us directly, if, for example, the CD ROM or one document was



missing although it was mentioned in the cover letter, and reminded us to send it.

Because we did so within the 10 days of formal review period, we did not receive a

respective deficiency letter. Not only once, they also took the opportunity to request

additional information in their confirmation of formal correctness without delaying the

start of the review period.

Most of the formal deficiencies refer to the CTA, which are, among others:

• All IMPs should be listed for which information will be gathered, also if used as

comparator

• If treatment is defined only by active substance, the marketing authorisation

number in the EU of one suitable marketed medicinal product should be

provided, and the respective SmPC should be submitted

• If the IMP is modified in relation to its marketing authorisation, at least a

simplified IMPD must be provided; the SmPC will not be sufficient

• Different strengths and dosage forms should each be mentioned as single

IMP, even if used as several dilutions of one prepared mixture

• If question F.3.3.2 – “women of childbearing potential using contraception” is

ticked “yes”, also question F.3.3.1 – “women of child bearing potential” must

be ticked “yes”, because they are in principle also of childbearing potential,

even if they use contraceptive measures

• In case of multi-centre trials only trials sites in the EU should be listed in

section G.1 and G.2

• In section G.3 local laboratories for the trial sites of section G.1 and G.2

should be listed, and also central laboratories, even if not situated in the EU, if

providing services for at least one of the EU sites

• In section G.4 all trial related duties should be specified, even if provided

through organisations in non-EU countries

• In section D.8.2 only the manufacturer should be listed, who is responsible for

batch release



• Name of active substance in section D.3.8 should be congruent to IMP (here:

“Insulin human” should be changed into “Insulin lispro”)

• In section D.3.4 the pharmaceutical form should be specified exactly (here:

“Powder for solution for injection” should be changed into “Powder and solvent

for solution for injection”)

Contentual Deficiencies

The focus of the BfArM review lies more on the medical and scientifically aspects of

protocol and IMP, rather than on ethical aspects of the trial. Therefore, the fields of

contentual deficiencies vary from those of the EC. In the following, I will just refer to

those documents, which may cause the main queries.

Possible contentual faults regarding the protocol could be:

• The chosen doses of the IMP should be justified, and the maximum dosage

should be stated

• Dose escalations should be stopped, as soon as the MTD (maximum tolerable

dose) will be reached; for this purpose the MID (minimum not tolerated dose)

must be defined and determined as stopping criteria

• In- and exclusion criteria should consist of contraindications of all IMPs, this

includes also the comparators

• Intervention criteria should be balanced carefully, defined exactly, and justified

as appropriate, including lower and upper limits, for example with regard to

- age groups (especially regarding concomitant medication and

accompanying illnesses)

- increase of laboratory values

- homogeneity of groups (e.g. body mass index)

- infection, allergies, and asthma

- women of childbearing potential or postmenopausal women (details and

definitions are given in ICH Topic M 3 [30])



• Documentation of medical history (here: accompanying illnesses in diabetics

such as retinopathy and polyneuropathy) should not predate by more than 3

months

• Interaction of IMP and contraceptive medication (Pearl Index should be < 1%)

should be considered

• In early phase trials in- and exclusion criteria should be limited as appropriate,

and close monitoring of participants, perhaps in-house where indicated, will be

mandatory

Possible contentual faults of the IMPD could be:

• Impurities should be listed in detail, not only the total amount should be limited

• In phase II trials development and validation studies on possible interactions

between the primary container and the contents should be presented

• Stability tests with the intended primary packaging for the marketed product

should be performed

• Conditions for transportation of the IMP should be specified

• For planned multiple use of solvents (here: lyophilisate) the requirements for

preservation should be taken into account

• Setting of the limits to potential genotoxic impurities should be based on

“Question & Answers on the CHMP Guideline on the Limits of Genotoxic

Impurities” [36]

• The germinal limit should be indicated prior to filtration

• IMPs without preservation should be reconstituted in germ-poor surrounding,

and used as soon as possible

• High concentration levels of preservations should be justified (here: 2.0 mg/mL

meta-cresol, instead of 1.5 mg/mL, which was regarded as sufficient by

BfArM)

• The qualitative composition of a hard gelatine capsule should be indicated



• Data to toxicokinetics should be submitted in tabular form for traceability

• In case of significant light absorption, the IMP should be tested for

phototoxicity and participants should be informed about possible risks

Possible contentual faults concerning the manufacturing licences could be:

• All manufacturers/importers must be nominated according their activities, and

the respective licences should be added

• The manufacturing licence must be issued by the competent authority of the

respective state, should be valid, and refer to all activities needed for the

purpose

• The details regarding manufacturers and importers should be consistent in all

documents

• If more than one manufacturing licence is submitted, the role of each

manufacturer should be defined clearly, especially the responsible party for

batch release (consistent to the application form)

Possible contentual faults concerning the labels could be:

• Instead of “Haltbarkeitsdatum” (best-before date) the term “Verwendbar bis”

(expiry date) should be used

• Instead of “Chargennummer” (lot number) the term “Ch.-B.” (batch name)

should be used

• Instead of “Raumtemperatur” (room temperature) the concrete temperature

level should be stated

• The label should consist of the dosing instructions, or alternatively a reference

to an accompanying document or the advice of the investigator should be

inserted

• If participants take the medication home, the advice “Keep away from children”

must be printed onto the labels; if medication will only admitted at the trial site,

a respective confirmation should be given (e.g. in the cover letter)



• All draft labels should present a random number or any other identification

code of the participant receiving this medication, otherwise a reference to an

accompanying document must be given

• The amount of active substance must be stated correctly (here: sitagliptin

phosphate 100 mg had to be replaced by sitagliptin 100 mg, because pursuant

to the SmPC “Each film-coated tablet of JANUVIA contains 32.13, 64.25, or

128.5 mg of sitagliptin phosphate monohydrate, which is equivalent to 25, 50,

or 100 mg, respectively, of free base…”

2.6 Notification according to § 67 AMG

According to § 67 German Drug Law (AMG) [22], the trial will have to be notified to the

local and, in the case of clinical trials in humans, also to the responsible competent

authority. The reason for this notification is to give these authorities the possibility to

monitor the clinical trial sites regarding GCP and GMP compliance.

2.6.1 Notification to Local Authorities

Responsibilities

In North Rhine-Westphalia, there are two local authorities in place, on the one hand

the Inspektorat für klinische Prüfstellen in Nordrhein-Westfalen (Inspectorate for

clinical trial sites in North Rhine-Westphalia), and on the other hand the

Bezirksregierung (Regional Council), both in Düsseldorf. As already described in the

preface, we normally have to notify our activities to both of these authorities. Just in

the case of multi-centre trials, when we are only acting as one of several trial sites

without further obligations, or in case of an amendment to the investigational site (e.g.

an additional investigator), the notification must only be sent to the Inspectorate.

According to § 12 GCP Ordinance, Anzeige-, Dokumentations- und

Mitteilungspflichten des Prüfers (Investigators’ duties to report, keep records and

notify) [41], and § 67 German Drug Law, Allgemeine Anzeigepflicht (General

notification requirement) [22], the investigator is responsible for the notifications to the

local authorities.



The investigator(s) may delegate this duty to the sponsor (which is common practice

in multi-centre trials) but nevertheless, this delegation must be documented. In our

experience, for a trained CRO and/or trial site, it is easier to make these notifications

on their own, because all documents will be kept in-house, and no tracking of

notifications will be necessary. For example, we had not only one incident, where we

had to insist on the necessity of notifying substantial amendments to the local

authorities, which is explicitly determined in § 12(1)3 GCP Ordinance [41] and §

67(3)1 German Drug Law [22].

Furthermore, our SOPs specify the notification process together with the related

documents as part of the trial investigator file (TIF), so we would have to ask the

sponsor to forward the correspondence with Inspectorate and Regional Council. This

is much more time-consuming than to keep the process at the site, especially, when

there are templates for the notification form and the cover letters in place. These cover

letters may be just a short reference to the attached notification form, and only one

paper copy is required. If there is any further documentation needed, the authorities

will contact the notifier directly.

Required Documents

The following information must be provided to the authorities in charge:

• Name, address, and professional title of the investigator obligated to report

• Designation of the competent federal authority and date when the

authorisation was granted and, where applicable, dates of authorisations of

subsequent amendments pursuant to § 10(1) GCP Ordinance [41]

• Designation and address of the competent Ethics Committee as defined in

§ 42(1)1 and 2 German Drug Law [22], date of its favourable opinion and,

where applicable, dates of authorisations of subsequent amendments

pursuant to § 10(1) GCP Ordinance [41]

• Designation and address of the Ethics Committee responsible for the

investigator and the trial site, and date of its opinion in this regard (in case of

multi-centre trials)



• EudraCT number of the trial

• Name or corporate name and address of the sponsor and, where applicable,

his representative in the EU/EEA

• Name and address of the co-ordinating investigator, and of the principal

investigator

• Name and address of involved laboratories/technical facilities

• Full title of the protocol including protocol code and objective

• Indication being tested

• Nature of the clinical trial and its conduct, including details of special

characteristics of trial participants to which the special conditions as defined in

§ 41 German Drug Law [22] apply

• Intended commencement and prospective duration of the trial

• Name, strength, pharmaceutical form, medically active ingredients, and route

of administration of the IMP

• Information as to whether the provisions of the laws relating to narcotics

(Betäubungsmittelrecht), to genetic engineering (Gentechnikrecht), or radiation

protection (Strahlenschutzrecht) must be observed, or whether it concerns

somatic gene therapy or genetic diagnostics

• Quantity and nature of comparator products used in the trial

For this purpose, a specific form (ZLG Formular, with three appendices in case of

multi-centre trials with several trial sites, other involved parties such as laboratories,

and involved ECs) may be downloaded from the homepage of the Zentralstelle der

Länder für Gesundheitsschutz bei Arzneimitteln und Medizinprodukten – ZLG (Central

Authority of the Länder for Health Protection with regard to Medicinal Products and

Medical Devices) (URL:https://www.zlg.de/arzneimittel/dokumente.html), where

detailed information is provided in the download area, and where a list of all potentially

involved authorities can be found.

http://www.zlg.de/download/AM/EFG/EFG05/Formular_Anzeige_KP_Par67AMG_V06.dot

https://www.zlg.de/arzneimittel/dokumente.html

http://www.zlg.de/cms.php?PHPSESSID=52c03edb6ca056856c2572735de48f61&mapid=102&hmp=6

http://www.zlg.de/download/AM/EFG/EFG05/GCP-Inspektorate-2009.pdf

http://www.zlg.de/download/AM/EFG/EFG05/GCP-Inspektorate-2009.pdf



The current version of the German template of the ZLG form will be provided in Annex

12.

After receipt of BfArM approval and positive opinion of EC(s), but prior to the start of

the clinical trial, the notification must be sent to all affected local authorities.

Any amendment must be notified as well, and should be included in the first version of

the form by ticking “Änderungsanzeige“ (Notification of amendment) instead of

“Anmeldung“ (Announcement) in section 5 of the form, giving the reason for the

amendment, and including the dates of the approval in section 7, and the positive

opinion in section 8, respectively.

After the end of the clinical trial, this date (in the format MM/YYYY) will have to be

inserted into the form in section 14. For mono-centre trials, the tick in section 5 should

be made for “Abmeldung der Gesamtstudie“ (Logoff of the whole trial), whereas in the

case of multi-centre trials each of those trial sites mentioned in section 6 should be

logged off, which have already finished their participation in the trial, and “Abmeldung

von Prüfstellen gemäß Ziffer 6“ (Logoff of trial sites according to number 6) should be

ticked.

This notification must be executed within 90 days after the regular end of the trial,

either for the trial site or for the complete trial. In case of premature terminations

(suspensions or interruptions), the notification must be submitted within 15 days,

stating the reasons for this decision.

2.6.2 Notification to BfArM

Responsibilities

According to § 67 German Drug Law, Allgemeine Anzeigepflicht (General notification

requirement) [22] and § 12 GCP Ordinance, Anzeige-, Dokumentations- und

Mitteilungspflichten des Prüfers (Investigators’ duties to report, keep records and

notify) [41], the investigator is also responsible for the notifications to the competent

authority in charge. As outlined before, the investigator(s) may delegate this duty to

the sponsor. Nevertheless, this delegation must be documented for notifications to the

competent authority as well.



The approval of the competent authority is not sufficient to fulfil this obligation, but this

is an independent administrative act, which must be executed before the start of the

trial, prior to the implementation of substantial amendments and also in case of the

notification of the end of the trial.

Required Documents

For notifying the trials to BfArM, it is accepted to just send a copy of the notification

form sent to the local authority, together with a short cover letter stating the reason of

the notification (start, substantial amendment, or end of the trial). For this purpose, we

use the subject lines of our cover letter for the application for approval of a clinical trial

(stating the EudraCT number, the protocol ID, and additionally the reference number

of BfArM,), so that tracking of the documents will be easy for the person dealing with

the case. As further facilitation of this process, no CD ROM with pdf files will be

required.



3 Requirements During the Trial

3.1 Amendments

After the clinical trial has commenced, changes to the protocol, other documents, or

procedures may be implemented according to article 10(a) of Directive 2001/20/EC

[11]. With regard to regulatory requirements, the sponsor has to decide whether the

amendment should be classified as substantial or not. Substantial amendments must

be submitted to that EC (as “Information”) and/or competent authority (as

“Notification”), which have reviewed these documents or procedures already within the

initial application process. Therefore, in Germany a significant change for example to

the IMPD will only have to be notified to the competent authority, whereas a change in

the conditions of the subject’s insurance, or any information regarding the trial site or

the investigators should only be sent to the concerned EC for the request for a positive

opinion. A notification/information of the other party is not needed and not desired,

anyway.

In contrast to the initial application, where no such rule exists, the information and

notification, respectively, of substantial amendments should be submitted in parallel to

EC and competent authority.

Both EC and BfArM will only accept amendments, once the initial application process

had finished. Prior to approval, solely those changes are allowed that refer to formal or

contentual deficiency letters.

3.1.1 Substantial Amendments

As outlined in § 10 GCP Ordinance [41], amendments are regarded as substantial and

must be approved by the competent authority and/or the Ethics Committee prior to

their implementation, if one of the following conditions is given:

• The amendment is likely to have an impact on the safety of the trial

participants



• The amendment is likely to change the interpretation of the scientific

documents where the trial bases on, or the scientific validity of the results may

be affected

• The amendment is likely to change the management or the conduct of the trial

• The amendment is likely to affect the quality or safety of the IMP(s)

• In case of involvement of IMPs derived from or containing of genetically

modified organisms, the amendment is likely to change the risk assessment

for non-affected persons or the environment

Sometimes, it is not easy to decide about the substantiality of a change, so the

sponsor may want to make use of legislative guidance. In the detailed guidance for the

application to the competent authorities [7] a list of examples can be found to which

extent an amendment will be regarded as substantial or not. Apart from that, the

sponsor may ask BfArM for advice regarding a proposed amendment – this advice will

be given without any fees, and might help to judge an amendment as substantial or

non-substantial.

Typical substantial changes to the protocol would be:

• Change of main objective

• Change of primary or secondary endpoint subject to significant impact

• New toxicological or pharmacological data or new (significant) interpretation of

existing data

• Change of the definition of the end of the trial, even if the trial has already

ended

• Addition of trial arms or placebo groups

• Change of in- or exclusion criteria with significant impact

• Change of IMP / or dosing of IMP / or route of administration (e.g. from oral to

subcutaneous)

• Reduction of monitoring frequency



Typical substantial changes to the IB would be:

• Changes to the safety information referred to in the annual safety report

• New toxicological or pharmacological data, or new interpretation of existing

data significant for the investigator

Typical substantial changes to the IMPD would be:

• Changes of manufacturing processes, test procedures, or manufacturing sites

• Changes of specifications of medicinal product or excipients

• Prolongation of shelf life

Typical substantial changes to other documents would be:

• Change of sponsor/legal representative

• Withdrawal or suspension of marketing authorisation of an IMP

In addition to preparing the changing documents, a specific notification form must be

filled out, which gives a brief overview about the proposed amendment. This form may

be downloaded from the EudraCT homepage be clicking on “Download CT

Amendment Form”. This link leads to EudraLex – Volume 10, Clinical trials guidelines

[20], where a pdf or word version of the form is provided in Chapter I: “Application and

Application Form”.

The following sections will have to be completed, but some of them only, if applicable:

• Type of notification (i.e. concerned MS, and if EC or competent authority is

affected)

• Trial identification (e.g. EudraCT number and protocol ID)

• Identification of the sponsor (and legal representative, if applicable) and the

applicant (either for request to EC or to the competent authority)

• Substantial amendment identification (e.g. code number, version, affected

documents, and reason)

• Description of each substantial amendment



• Change of clinical trial site(s)/investigator(s) in the concerned Member State

• Change of instructions to CA for feedback to sponsor (only for amendments to

CA)

• List of appended documents

• Signature of the applicant (either for request to EC or CA)

It may be worthwhile to prepare a template of this form with the relevant contact

details of the applicant, so that these details will not have to be inserted again every

time. For the description of the amendment in section F of the form, it may be clearer

to append a separate document, giving this information, rather than to include old and

new wording right into the form. The designated space in the form, as given below,

offers only little room in the columns.

Previous and new wording in track change modus

New wording Comments/explanation/reasons for substantial amendment

Table 1: Section F of “Notification of a substantial amendment form”

A completion of the form may be administrable for short amendments with only few

text passages, but for considerable changing of the wording the insertion of text in

these columns, moreover in track change modus, would not really facilitate the

tracking of the versions. By inquiry at EC and BfArM, we could clarify that a reference

to an accompanying document is not only accepted, but also preferred.

The current version of this notification form will be attached as Annex 13.

Ethics Committee

The positive opinion of the responsible EC will be required for any amendment

affecting the documents as outlined in § 7(2,3) GCP Ordinance [41]. These are those

ones, which have already been reviewed by the EC within the application process for

a positive opinion of the clinical trial.



Timelines and Formal Requirements

According to Article 10(a) of Directive 2001/20/EC [11], the Ethics Committee is

required to give an opinion on a proposed substantial amendment within 35 days. In

Germany, the EC will review the documents within 20 days (no matter, if mono- or

multi-centre trials) – also for substantial amendments a confirmation of formal

completeness will be provided.

It is in the responsibility of the sponsor to decide, whether an amendment is regarded

as substantial, and which documents shall be provided for review. Therefore, the

check of formal completeness extends in my understanding mainly to the presence of

the agreements of sponsor and principal investigator to this amendment, and if all

documents mentioned in the cover letter and/or the notification of amendment form

are part of the submission package.

The documents should be sent tenfold as paper copies and on CD ROM as pdf files.

At present, no submission of a changed application form should be provided to our

EC, because the primary function of this document is mainly to get a quick overview of

the main issues and responsibilities of the trial in the initial application process. As a

result, the newly sent form will not be reviewed again, and therefore should not be

sent. In a recent telephone call, I have learned that the EC of the Medical Association

North Rhine is working on a new SOP with regard to the application form. After that

implementation it might be possible that the application form should be sent each time

it has been updated.

BfArM

The authorisation of BfArM will be required for any amendment affecting the

documents as outlined in § 7(2,4) GCP Ordinance [41]. These are those ones,

comparable to the amendment procedure with the EC, which have already been

reviewed by BfArM within the initial application process for an authorisation of the

clinical trial.




Although there is no deadline set in Directive 2001/20/EC [11], BfArM will also review

the documents within 20 days for both mono- and multi-centre trials. In contrast to the

EC, no letter of formal completeness will be sent. This may be subject to the fact that

all our amendment submissions were considered to be valid, and in case of missing

documents, such a letter would be sent to the applicant, but I have never received

one.

The documents should be sent fourfold as paper copies and on CD ROM as pdf files.

If there was an update to the application form, the updated xml file should be sent as

well.

If BfArM has not raised grounds for non-acceptance within these 20 days, the

proposed amendment may be implemented (implicit approval) – we have always

received an approval, though.

3.1.2 Non-substantial Amendments

According to Directive 2001/20/EC [11], no notification to competent authorities or

submission of information to the EC is obligatory in case of non-substantial

amendments.

To decide, whether an amendment can be regarded as non-substantial, the list in the

detailed guidance [7] may be of great help for the applicant. These issues, among

others, can be considered as non-substantial:

• Changes to the identification of the trial (e.g. change of title, etc.), minor

clarifications to the protocol or correction of typographical errors

• A minor increase in the duration of the trial (< 10 % of the overall time of the

trial)

• An increase in duration of > 10 % of the overall time of the trial, provided that:

- the exposure to treatment with the IMP is not extended,

- the definition of the end of the trial is unchanged, and

- monitoring arrangements are unchanged



• A change in the number of clinical trial participants per trial site, if the total

number of participants in the Member State concerned is identical, or the

increase/decrease is insignificant in view of the absolute number of

participants

• A change in the number of clinical trial participants in the Member State

concerned, if the total number of participants is identical or the

increase/decrease is insignificant

• Additional safety monitoring, which is not part of an urgent safety measure

• Any change of persons other than the sponsor or his legal representative, or

changes to the internal organisation of the sponsor, or of the persons to whom

certain tasks have been delegated

Ethics Committee

In contrast to other ECs in Germany, the EC of the Medical Association North Rhine

sticks conclusively to the requirements of the Directive 2001/20/EC [11], and the GCP

Ordinance [41]. The submission of non-substantial amendments or any documents

“for information only” will be rejected together with a definition of substantial

amendments, and a statement that the Committee has not reviewed the documents.

In order to clarify this position to the respective sponsor, any auditors or other

interested parties, a not trial-related version of this statement will be added to the TIF

and TMF of the respective trial in case of non-substantial amendments.

This procedure is not in line with the information provided at the homepage of the EC

Working Group, where the following information in the Resolution 4 [38] (see attached

as Annex 14) can be found:

• Non-substantial amendments should only be sent to the responsible EC

• Non-substantial amendments are not subject to submission but should be

documented thoroughly, archived in the TIF/TMF, and may be reviewed by the

EC at a later point of time



• Informed consent form, information sheets or other documents, which are

planned to be given to the trial participants should always be sent to the EC,

even in case they are non-substantial

BfArM

For BfArM this procedure is not as decisive as for the EC of the Medical Association

North Rhine. Although according to section 107 of the guidance document [7] there is

no obligation to submit non-substantial amendments, on the BfArM homepage you will

find the information that all amendments should be submitted “for information”, which

lead to an alteration of the initial application or the application form. Moreover, the

classification of the examples to non-substantial amendments “[e.g. additional trial

sites (zusätzliche Prüfzentren), change of the PI (Wechsel des Hauptprüfers), change

of the name of the sponsor, or of the contact person (Änderungen des Namens des

Sponsors oder Änderung der Kontaktperson)]” is not really unambiguous.

Overall, without going into details, it seems to be of some importance for BfArM to

receive these notifications, even if in contrast to the guidance document [7] and

Directive 2001/20/EC [11], and even if not entirely consistent according to their own

website. Therefore, it may be defined by sponsor and supportive CRO to just send the

information and to leave the decision up to BfArM, if they need or want the information

or not. However, BfArM will not send a confirmation letter or receipt to non-substantial

amendments.

Nevertheless, at least once, we have submitted a non-substantial amendment (as in

the view of the sponsor), but BfArM told us in contrast that they consider this

amendment to be substantial, that we should submit additional documents, and that

we would have to wait for their approval.

3.1.3 Change of Investigational Site

In the course of a clinical trial, a change of the investigational site may become

necessary, and should or should not be notified to EC and/or competent authority.



Ethics Committee

With the application documents to EC, some information to the feasibility of the trial

site should be provided. If the trial site is regarded as eligible for conducting the

respective clinical trial, any alteration of the given conditions may lead to a different

opinion. The sponsor will have to decide, whether the change of the given background

leads to a substantial amendment. This will always be the case, if the principal

investigator in a mono-centre trial will change (and for the change of the coordinating

investigator in multi-centre trials). But also for additional research physicians acting in

the trial site according to Resolution 4 of the EC Working Group as of November 2005,

last updated in June 2008, the positive opinion of the EC must be obtained:

“Änderungen von Prüfern in einer Prüfstelle: Die Änderung des Leiters der

klinischen Prüfung, des Hauptprüfers oder des einzigen Prüfers in einer Prüfstelle

oder die Meldung zusätzlicher Prüfer sind bewertungspflichtige, nachträgliche

Änderungen (GCP-V § 3 Abs. 2c und § 10 Abs. 1 Ziffer 3)“. [38]


For the notification of additional investigators, the same requirements as for the initial

application documents apply. Therefore, the current CV, a GCP certificate, and the

confirmations (e.g. financial disclosures) as for the other investigators are necessary.

After submission of an investigator amendment, a receipt of these documents, and

confirmation of formal completeness will be sent as well.

As for all amendments, the documents should be sent tenfold as paper copies and

electronically on CD ROM. The review time will be 20 days in the case of mono-centre

trials (for multi-centre trials the review period will be extended to 30 days, because the

leading EC will give its opinion only after consultation with the involved EC), and the

investigator must not work within that trial prior to receipt of EC’s positive opinion.

BfArM

Since BfArM is not responsible for the review of the eligibility of the trial site, no

change of the local conditions (i.e. personnel, resources, facility, etc.), and only rarely



in the composition of the investigators must be notified to the competent authority.

This is only the case if

• the principal investigator in a mono-centre trial will change

• the coordinating investigator in a multi-centre trial will change

If the investigational site does not longer take part in a multi-centre trial, this must be

notified according to § 67 German Drug Law [22] (see above, section 2.6.2

“Notification to BfArM”), though.


BfArM will review the notification of amendment within 20 days, both for mono- and

multi-centre trials. The documents should be sent fourfold as paper copies, and

electronically as pdf and xml file – due to the change in the application form – on CD

ROM.

No confirmation of formal completeness will be sent, merely only the approval or

possibly a letter stating contentual deficiencies of the amendment.

3.2 AE and SUSAR Reporting

According to § 13 GCP Ordinance [41], the sponsor is responsible for the

documentation of any adverse event (AE), or serious adverse event (SAE), he was

informed about by the investigator(s). The documentation should on request be

passed on to the competent authority of any Member State of the EU (and of the EEA)

participating in the clinical trial.

In case of a suspected unexpected serious adverse reaction (SUSAR), a notification

of the Ethics Committees and the competent authorities of the participating countries

(EU and EEA), and of the involved investigators must take place within 15 days after

awareness. Content and format are described in the Detailed guidance on the

collection, verification and presentation of adverse reaction reports arising from clinical

trials on medicinal products for human use [9].



In case of death, or if the adverse reaction was life-threatening, this notification must

happen immediately, but at least within 7 days (expedited reporting). Within further 8

days, any additionally available relevant information should be transferred to the

involved parties.

If there are other circumstances that lead to an updated risk benefit assessment, the

sponsor has to inform the involved competent authorities and ECs within 15 days. The

examples given below should therefore be assessed by the sponsor regarding their

relatedness and relevance. Related issues may be

• individual case reports of suspected adverse reactions (SARs) with

unexpected outcome

• increased frequency of SARs that are regarded as clinically significant

• suspected unexpected serious adverse reactions (SUSARs) after a trial

participant has already ended the participation

• circumstances in relation with the trial conduct, or the development of the

investigational medicinal product (IMP), which could negatively affect the

safety of the trial participants

All transferred data should be pseudonymised by using the identification code of the

respective trial participant.

According to the guidance mentioned above and the Verordnung über die

elektronische Anzeige von Nebenwirkungen bei Arzneimitteln (Ordinance on the

electronically notification of adverse reactions of medicinal products) [42], the

notification to the competent authorities should be made electronically (except the

sponsor is no pharmaceutical company or delegate), and additionally in paper version,

as long as the concerned authority does not inform the sponsor to the contrary.

In connection with AEs, SAEs, and SUSARs, the investigator has the obligation to

inform the sponsor immediately, except the protocol allows a deferred reporting. The

definition of AEs, SAEs, SARs or SUSARs, and the timelines for reporting in

connection with the IMP should always be given in the protocol. After the immediate

report, further detailed information should be provided as soon as possible. In case of



death of a trial participant, the investigator should provide the relevant information to

the involved parties [leading EC (and participating ECs in case of multi-centre trials),

competent authority, and sponsor].

Normally, SUSAR reporting will be done by the sponsor’s pharmacovigilance

department, or a contracted company, as it is required by law. According to § 63

German Drug Law, “any pharmaceutical company placing medicinal products (under

the terms of § 2) on the market, shall appoint a qualified person who is resident in a

member state of the European Union having the required expert knowledge and the

reliability necessary for exercising his/her function (graduated plan officer) to set up

and manage a pharmacovigilance system and to collect and evaluate notifications on

medicinal product risks that have become known and co-ordinate the necessary

measures.” [22]

But nevertheless, several times we were requested to send SUSAR reports also to the

EC, which should only be sent to BfArM (and other competent authorities, if

applicable) according to the definition given above. In case of the EC of the Medical

Association North Rhine, these reports were sent back with an accompanying letter,

stating that the EC is no authority for pharmacovigilance. Only in case the SUSAR

affects the clinical trial that was reviewed previously by the EC, and is therefore in its

responsibility, it would have been accepted together with a statement of the sponsor to

which extent the trial participants may be vitiated or endangered.

3.3 IB Update

According to the current Guideline for Good Clinical Practice [28], and the

Commission Directive 2005/28/EC [4], the sponsor should review the IB annually and

revise it if necessary, or in case relevant new information becomes available during

the conduct of a clinical trial. If the new information is of relevance for the classification

of SUSARs, the IB or the new information should be sent to the investigators for

information (as so called “Dear Investigator Letter”).

If the update is in fact regarded as a substantial amendment, it must also be

transferred to the involved competent authority(ies), and EC(s) for review and



approval. For this purpose, the amendment notification form from EudraCT should

also be used. In section E (Substantial Amendment Identification) the “Sponsor’s

substantial amendment code number, version, date for the clinical trial concerned”

should be filled in with the date and version of the updated IB, and the type of

amendment should be declared as “Amendment to other documents appended to the

initial application form”. As “Reasons for the substantial amendment” E.3.7 should be

ticked “yes” and “Update of the Investigator’s Brochure (plus the name of the

respective IMP)” should be inserted.

However, the update of an IB does not always have to be regarded as substantial

amendment, and not in any case it should be submitted to the authorities or to the

EC(s). Nevertheless, we experienced in contrast that most IB updates were submitted

to BfArM regularly, and very often also to the EC. Some sponsors have standard

operating procedures (SOPs) in place that require such an approach, even if not

required by the authorities and the EC. In case of the EC of the Medical Association

North Rhine, only substantial IB amendments will be accepted – not only “for

information”.

3.4 Yearly Report

According to ICH-GCP, “The investigator should submit written summaries of the trial

status to the IRB/IEC annually, or more frequently, if requested by the IRB/IEC.” [28]

In Germany, this clause is given in § 13(6) GCP Ordinance [41]: “Der Sponsor hat der

zuständigen Ethik-Kommission, der zuständigen Bundesoberbehörde und den

zuständigen Behörden anderer Mitgliedstaaten der Europäischen Union und anderer

Vertragsstaaten des Abkommens über den Europäischen Wirtschaftsraum, in deren

Hoheitsgebiet die klinische Prüfung durchgeführt wird, während der Dauer der Prüfung

einmal jährlich oder auf Verlangen eine Liste aller während der Prüfung aufgetretenen

Verdachtsfälle schwerwiegender Nebenwirkungen sowie einen Bericht über die

Sicherheit der betroffenen Personen vorzulegen.“

For the submission of the annual safety report (ASR), which should include a list of

SUSARs that have occurred during the reported period, the amendment form will not



have to be used in any circumstance. Just if the report’s data require a change of

other documents, e.g. the protocol or the IB, and this change is regarded as

substantial, an amendment should be issued and submitted (Article 17(2) of Directive

2001/20/EC) [11]. The Detailed guidance on the collection, verification and

presentation of adverse reaction reports arising from clinical trials on medicinal

products for human use [9], including information to content and format of annual

safety reports, can be found on the website of the European Commission. According

to this guidance, the ASR should have three parts:

• Analysis of the subjects’ safety in the concerned clinical trial

• A line listing of all suspected serious adverse reactions (including all SUSARs)

that occurred in the concerned trial, including also serious adverse reactions

from third countries

• An aggregate summary tabulation of suspected serious adverse reactions that

occurred in the concerned trial



4 End of Trial Notification

4.1 Responsibilities

According to the European guidelines and the GCP Ordinance § 13(8) [41], the

sponsor has to notify the interruption, the premature termination, or the regular end of

the clinical trial to the competent and local authorities, and to the responsible EC(s).


An interruption or a premature termination must be notified within 15 days by giving

the reasons for the interruption or termination.

The regular end of the trial must be notified within 90 days – the definition for the end

of the clinical trial should always be given in the protocol, otherwise the last visit of the

last participant will by definition be regarded as the end of the trial.

Whereas only the end of the trial in all concerned countries (EU Member States or

third countries) must be notified to BfArM and EC, the local authorities Inspectorate

and Regional Council must be informed about the end of the trial in the trial site, which

they have to supervise. In case of global clinical trials, a trial site in a third country may

just begin with recruitment due to local problems or requirements, whereas the

German site may have already come to the end of the trial. If this is the case, the local

authority should be informed within 90 days about this trial termination.

It is advisable to wait with the notification until the deadline has nearly expired

because sometimes additional activities may have to be performed – provided that

they are allowed per protocol. This would be impossible or at least difficult, if the trial

has already been notified as terminated.



4.3 Required Documents

BfArM and EC

In case of an interruption, the “Substantial amendment notification form” from

EudraCT [15] should be used, and information should be provided in section E.4

“Information on temporary halt of trial”. The restart of the trial will definitely be

regarded as substantial amendment, and must not take place prior to approval

through BfArM and positive opinion of the EC.

In case of a premature termination, the “Declaration of the end of trial form” from

EudraCT [15] should be used by ticking “yes” to section D.2 “Is it an early

termination?”, stating the reasons for the termination, and the consequences for the

trial participants in sections D.2.1 to D.2.2.3.

If necessary to ensure the participants’ well-being, safety measures may be

implemented prior to the notification both in case of interruption, and in case of

premature termination.

The regular end of the trial will also be notified by using the “Declaration of the end of

trial form” but in contrast to a premature termination, the date for the end of the trial

will be given in section D.1 by ticking “no” to D.2.

The current version of the “Declaration of the end of trial form” will be provided as

Annex 15.

For BfArM, the notification of the end of the trial should also take place according to §

67 German Drug Law [22]. For this purpose, again the ZLG form (see chapter 2.6.2)

may be copied, and provided together with a short covering letter. This notification

informs BfArM about the termination in single trial sites apart from the notification of

the end of the whole trial.

Local authorities

For the notification to the local authorities, the already formerly mentioned ZLG form

should be used once again by ticking “Abmeldung der Gesamtstudie” (Logoff of the



complete trial) or “Abmeldung von Prüfstellen” (Logoff of trial sites), whatever is

applicable, in section 5 “Grund der Anzeige” (Reason for notification), and adding the

date (month and year) in section 14.

Because the ZLG form was filled out at least for the notification of the start of the trial,

it may be used once again with all inserted information (except information to any

amendment in section 5 – this should be deleted to make clear that no amendment

will be notified but the end of the trial).



5 Report

In § 13 GCP Ordinance, Dokumentations- und Mitteilungspflichten des Sponsors

(Investigators’ duties to keep records and notify) [41] it is defined that one year after

the end of the trial a summary of the clinical trial report (in this context mostly called

“synopsis”) must be submitted to competent authority and responsible EC. This report

should follow the requirements given in ICH Topic E3 – Note for Guidance on

structure and content of clinical study reports [26].

The synopsis should therefore give information to following topics:

• Name of sponsor and company

• Name of finished product

• Name of active ingredient

• Title of the study

• Investigators

• Study centre(s)

• Publication (reference)

• Studied period (years)

- (date of first enrolment)

- (date of last completed)

• Phase of development

• Objectives

• Methodology

• Number of patients (planned and analysed)

• Diagnosis and main criteria for inclusion

• Test product, dose and mode of administration, batch number

• Duration of treatment



• Reference therapy, dose and mode of administration, batch number

• Criteria for evaluation

- Efficacy

- Safety

• Statistical methods

• Summary – Conclusions

- Efficacy Results

- Safety Results

- Conclusion

• Date of the report

For future reports, the format will change and a DSUR (Development Safety Update

Report) shall be written. The CIOMS (Council for International Organizations of

Medical Sciences) Working Group have announced the publication of “The

Development Safety Update Report (DSUR): Harmonizing the Format and Content for

Periodic Safety Reporting During Clinical Trials.” [39] in 2006 and the respective ICH

Topic E2F, Development Safety Update Report [29] is currently in step 4 of

implementation. The goal of this approach is a global harmonisation of the currently

existing different formats: “The Development Safety Update Report (DSUR) … is

intended to be a common standard for periodic reporting on drugs under development

(including marketed drugs that are under further study) among the ICH regions.” [29].

The guideline shall come into operation in September 2011.


The synopsis should be sent as one paper copy and as pdf file on CD ROM to both

BfArM and EC together with a short covering letter stating the respective reference

number, the EudraCT number, and the trial ID.

In exceptional circumstances, it is possible to ask for a time extension for the

submission of the report. This may for example be the case, if the laboratories had



problems with analysing the samples. A short letter stating the instances will allow

BfArM and EC to check whether they could agree on such an extension of the

deadline. The responsible RA manager should remind the involved parties not to wait

too long for this request, but to send it in due time.



6 Helpers in Daily Work

There are many duties to perform in a regulatory department prior to the application

and during the course of a clinical trial, and many timelines must be adhered to.

Therefore, it is advisable to create templates of all necessary documents and cover

letters, to design checklists, and to have a tool in place that allows following up on all

timelines.

6.1 List of Documents

In our database, we have a “list of available documents” related to regulatory affairs

that may be needed in the course of the trial. On the one hand, these are partly

completed cover letters and templates of the relevant forms to the different authorities

(BfArM, Inspectorate, and Regional Council) and to the EC, and on the other hand,

these are SOPs and checklists that may be used for information and help.

For all documents, we have inserted a comment, for what purpose they will be

needed, and where they will be found. The comments may help the study teams that

are involved in the trials, to have a quick overlook on what may be needed for the

application and where they get further help.

Some of the documents are centrally stored in the document management system

(DMS), have a version number, and will be tracked; many others are stored only

electronically in the regulatory affairs folder. This facilitates for example the update of

the cover letters in case of deficiencies, when an answer could easily be included into

the template as standard without tedious update of the document in the DMS.

For documents, which are stored in the DMS, and have a document ID, a hyperlink is

inserted in the list, so that they can be called up easily.

One of these documents, called Antrags- und Anzeigeverfahren bei klinischen

Prüfungen (Application and notification procedures in clinical trials), is a description of

the application process to both EC and BfArM, and both for trials with medicinal

products and medical devices. This document is also used as SOP regarding several



topics, e.g. who is responsible for what, or for the requirement that the respective

principal investigator has to sign approvals or positive opinions prior to filing in the TIF.

6.2 Structure of folders

When a trial folder will be created, a specific structure is preset that should be

changed only when necessary. The levels of these folders are given below:

First level “Authorities”

Figure 17: Structure of folders “Authorities”

Second level BfArM

Figure 18: Structure of folders “BfArM”



Some folders of this second level are not yet numbered, because the number may

change due to formal or contentual deficiencies, and therefore additional folders with

numbers in between must be added.

If there have been amendments in a trial, an additional folder “Amendments” will be

created, and given the subsequent number. The subfolders should be numbered from

1. to x., to guaranty a chronological order. As you can see in the example below, there

may be several amendments of the same type, so a numeration in this respect is also

useful.

Figure 19: Structure of folders “BfArM / Amendments”

Third level BfArM [only for section 10, “Dokumente Einreichung“ (Documents

for submission)]

Figure 20: Structure of folders “BfArM / Documents for submission”

The documents in this third level are those ones that have been burnt to CD ROM, as

they are the ones, which have been printed and were stored in the submission folders.

For all submitted documents, no matter if with the initial application, any answer to



deficiencies or in case of amendments, applies the same. The identification of what

has been submitted is therefore very simple. The nomination of these subfolders is

both in German and in English to facilitate the transfer to the sponsor’s trial team (very

often not German-speaking).

Second level EC

Figure 21: Structure of folders “EC”

Some folders of this second level are not yet numbered, because the number may

change due to formal or contentual deficiencies, and therefore additional folders with

numbers in between must be added.

If there have been amendments in a trial, an additional folder “Amendments” will be

created, and given the subsequent number. The subfolders should be numbered from

1. to x., to guaranty a chronological order. As you can see in the example below, there



may be several amendments of the same type, so a numeration in this respect is also

useful.

For a possible subfolder “Amendments” applies again the same as for BfArM, but in

contrast to the example for BfArM given above, the non-substantial amendment here

was not submitted to the EC, but only stored electronically.

Figure 22: Structure of folders “EC / Amendments”

Third level EC [only for section 17, “Dokumente Einreichung“ (Documents for

submission)]

Figure 23: Structure of folders “EC / Documents for submission”



The documents in this third level are those ones that have been burnt to CD ROM, as

they are the ones, which have been printed and were stored in the submission folders.

For all submitted documents, no matter if with the initial application, any answer to

deficiencies or in case of amendments, applies the same. The identification of what

has been submitted is therefore very simple. The nomination of these subfolders is

both in German and in English to facilitate the transfer to the sponsor’s trial team (very

often not German-speaking).

Second level Inspectorate

Figure 24: Structure of folders “Inspectorate”

In case of the Inspectorate, and as subsequently shown for the Regional Council,

there are no more than three subfolders in the second level, because there are only

three types of notifications: First notification, notification of amendments, and

notification of the end of the trial. Both authorities will send confirmations to the

several notifications, including the respective invoice, but this may take several weeks

until receipt, especially as to the Regional Council (normally the Inspectorate is

working faster).

Second level RP (Regional Council)

Figure 25: Structure of folders “Regional Council”



Second level Insurance

Figure 26: Structure of folders “Insurance”

In case of the insurance, there are only two subfolders, because there will be an

application form and a cover letter in the subfolder “Korrespondenz”

(Correspondence), and the insurance documents for the trial participants will be filed

in the subfolder “Versicherungsunterlagen für Probanden” (Insurance documents for

trial participants). Out of this subfolder, the insurance documents will be printed for the

trial participants.

In case of further correspondence with the insurance company, there might be

subfolders in the correspondence folder, but this is rare.

6.3 Filenames

Of great help is also the relatively strict abidance to fixed file names. The document

“Benennung der Dateien für die Behörden” (Naming of files for the authorities)

provides an overview, how the files should be named when filing in the electronic trial

folder. For example, when the EC has sent a confirmation of formal complete receipt

by fax, the file name will be “Date (in the format YYYY-MM-DD)_Study

code_EC_Receipt formal complete submission.pdf”.

Word files (e.g. cover letter, application form, module 2) shall not be stored with a date

in the file name because they may change several times from the first draft to the final

version. Then the date would have to be changed each time, otherwise it would be

wrong after the first update.

This is useful only for pdf files, because they will not change any more. By dating as

many documents as possible, the letter of positive opinion from the EC, which lists all

submitted documents, may be checked more easily, whether all dates of the relevant

documents are stated correctly. Just a look at the date in the file name of the



respective document confirms the correctness. In case the dates differ, the pdf file

should be opened to verify the date in the file name. If the EC clerk has stated the

wrong date, the project manager or PI should be asked, if a corrected version of the

opinion letter shall be requested. This will always be the case, if relevant documents

are affected, such as the protocol or the IB.

Correspondence from and to the EC

Word Files PDF Files Studycode_Cover letter submission_EC

YYYY-MM-DD_Studycode_Cover letter submission_EC

YYYY-MM-DD_Studycode_EC_Receipt submission

YYYY-MM-DD_Studycode_EC_Formal deficiencies Studycode_Answer letter formal deficiencies_EC

YYYY-MM-DD_Studycode_Answer letter formal deficiencies_EC

YYYY-MM-DD_Studycode_EC_Contentual deficiencies

Studycode_Answer letter contentual deficiencies_EC

YYYY-MM-DD_Studycode_Answer letter contentual deficiencies_EC

YYYY-MM-DD_Studycode_EC_Charges trial

YYYY-MM-DD_Studycode_EC_Approval Studycode_Cover letter amendment Nr_EC

YYYY-MM-DD_Studycode_Cover letter amendment Nr_EC

Studycode_Notification form amendment Nr_EC

YYYY-MM-DD_Studycode_Notification form amendment Nr_EC

YYYY-MM-DD_Studycode_EC_Receipt amendment Nr

YYYY-MM-DD_Studycode_EC_Charges amendment Nr

YYYY-MM-DD_Studycode_EC_Approval amendment Nr

Studycode_Cover letter end of trial_EC

YYYY-MM-DD_Studycode_Cover letter end of trial_EC

Studycode_End of trial form_EC YYYY-MM-DD_Studycode_End of trial form_EC

YYYY-MM-DD_Studycode_EC_Confirmation end of trial

Studycode_Cover letter CTR_EC YYYY-MM-DD_Studycode_Cover letter CTR_EC

YYYY-MM-DD_Studycode_EC_Receipt CTR

Table 2: Filenames for correspondence “EC”



Correspondence from and to BfArM

Word Files PDF Files Studycode_Cover letter submission_BfArM

YYYY-MM-DD_Studycode_Cover letter submission_BfArM

YYYY-MM-DD_Studycode_BfArM_Receipt submission

YYYY-MM-DD_Studycode_BfArM_Formal deficiencies

Studycode_Answer letter formal deficiencies_BfArM

YYYY-MM-DD_Studycode_Answer letter formal deficiencies_BfArM

YYYY-MM-DD_Studycode_BfArM_Contentual deficiencies

Studycode_Answer letter contentual deficiencies_BfArM

YYYY-MM-DD_Studycode_Answer letter contentual deficiencies_BfArM

YYYY-MM-DD_Studycode_BfArM_Charges trial

YYYY-MM-DD_Studycode_BfArM_Approval Studycode_Cover letter amendment Nr_BfArM

YYYY-MM-DD_Studycode_Cover letter amendment Nr_BfArM

Studycode_Notification form amendment Nr_BfArM

YYYY-MM-DD_Studycode_Notification form amendment Nr_BfArM

YYYY-MM-DD_Studycode_BfArM_Receipt amendment Nr

YYYY-MM-DD_Studycode_BfArM_Charges amendment Nr

YYYY-MM-DD_Studycode_BfArM_Approval amendment Nr

Studycode_Cover letter end of trial_BfArM

YYYY-MM-DD_Studycode_Cover letter end of trial_BfArM

Studycode_End of trial form_BfArM YYYY-MM-DD_Studycode_End of trial form_BfArM

Studycode_Cover letter CTR_BfArM YYYY-MM-DD_Studycode_Cover letter CTR_BfArM

Studycode_ Notification § 67_ BfArM YYYY-MM-DD_Studycode_Notification § 67_BfArM

Table 3: Filenames for correspondence “BfArM”



Correspondence from and to the Inspectorate

Word Files PDF Files

Studycode_Notification trial_Insp YYYY-MM-DD_Studycode_Notification trial_Insp

Studycode_ZLG form_Insp YYYY-MM-DD_Studycode_ZLG form_Insp

YYYY-MM-DD_Studycode_Insp_Confirmation trial Studycode_Notification amendment Nr_Insp

YYYY-MM-DD_Studycode_Notification amendment Nr_Insp

Studycode_ZLG form amendment Nr_Insp

YYYY-MM-DD_Studycode_ZLG form amendment Nr_Insp

YYYY-MM-DD_Studycode_Insp_Confirmation amendment Nr

Studycode_Notification end of trial_Insp

YYYY-MM-DD_Studycode_Notification end of trial_Insp

Studycode_ZLG form end of trial_Insp

YYYY-MM-DD_Studycode_ZLG form end of trial_Insp

YYYY-MM-DD_Studycode_Insp_Confirmation end of trial

Table 4: Filenames for correspondence “Inspectorate”

Correspondence from and to the Regional Council (RP)


Studycode_Notification trial_RP YYYY-MM-DD_Studycode_Notification trial_RP

Studycode_ZLG form_RP YYYY-MM-DD_Studycode_ZLG form_RP

YYYY-MM-DD_Studycode_RP_Confirmation trial

Studycode_Notification amendment Nr_RP

YYYY-MM-DD_Studycode_Notification amendment Nr_RP

Studycode_ZLG form amendment Nr_RP

YYYY-MM-DD_Studycode_ZLG form amendment Nr_RP

YYYY-MM-DD_Studycode_RP_Confirmation amendment Nr

Studycode_Notification end of trial_RP

YYYY-MM-DD_Studycode_Notification end of trial_RP

Studycode_ZLG form end of trial_RP

YYYY-MM-DD_Studycode_ZLG form end of trial_RP

Table 5: Filenames for correspondence “Regional Council”



Correspondence from and to the Insurance Company


Studycode_Notification trial_Insurance

YYYY-MM-DD_Studycode_Notification trial_Insurance

Studycode_Notification form_Insurance

YYYY-MM-DD_Studycode_Notification form_Insurance

YYYY-MM-DD_Studycode_Subject insurance_Confirmation trial

YYYY-MM-DD_Studycode_Accident insurance_Confirmation trial

YYYY-MM-DD_Studycode_Notification end of trial_Insurance

Table 6: Filenames for correspondence “Insurance company”

In case, communication from the authorities will not be received electronically, but only

by mail, the letter should be scanned and stored in the respective folder as pdf file.

The list of file names as given above should not be regarded as obligatory, but just as

a hint. The name should be clearly understandable – that is what counts in the end.

Sticking to a relatively clear order also helps not to overwrite a file by mistake.

Generally, documents coming from the authorities will be stored by stating the name

of the authority right after the study code, as already listed above. Documents, which

will be sent to the authorities, will be stored by stating the authority’s name at the end

of the file name: Date_Study code_Cover letter submission_Authority (e.g.

BfARM).pdf”.

It is really obvious from the number of documents received in the course of a trial that

a chronological order, and definite file names are mandatory.

English nominations are not necessary for word documents, but this may be helpful,

though, because this name could then be transferred directly into the pdf file name.

This one should regularly be in English, so that a member of the project team or the

RAM can directly send this document to the sponsor who is very often not situated in

Germany.

By sorting the files with the date format “YYYY-MM-DD”, a chronological order can be

followed easily, and all persons involved in the trial can find the relevant



communication without delay. To follow the chronological order, letters and

confirmations that were received from the authorities will be filed without using further

subfolders.

For example, when opening the folder for EC, the subfolders are shown and beneath

them, the communication from EC is listed chronologically as shown below.

Figure 27: Structure of folders and files “EC”



6.4 Templates

Of enormous help are templates for recurring cover letters and notification forms. In

the course of the time, we have created many of such templates – in the following I

will just give an overview of what is possible. Nevertheless, before using any of these

templates, the inserted information must be checked each time, and should not be

taken for granted.

Templates for documents to EC (EK)

Figure 28: Templates for documents “EC”



Templates for documents to BfArM

Figure 29: Templates for documents “BfArM”

Templates for documents to the Inspectorate

Figure 29: Templates for documents “Inspectorate”

Templates for documents to the Regional Council (RP)

Figure 30: Templates for documents “Regional Council”



Templates for documents to the Insurance

Figure 31: Templates for documents “Insurance”

For the notification of a trial to the insurer, we use an e-mail template, stating the title,

the EudraCT number, and the trial ID. This allows the clerks of the insurance to copy

these data directly from the e-mail – typing errors will therefore be minimized.

6.5 FAQ List

Other “little helpers” are growing lists of possible faults and deficiencies that will be

compiled over the time. These lists should help to avoid making the same mistakes

recurrently.

For BfArM, the lists range from formalities over issues with the protocol, the

application form, or the labels.

Figure 32: FAQ list “BfArM”

For the EC, the topics differ a bit, depending on the different documents they have to

review:

Figure 33: FAQ list “EC”



Many of the possible subjects have already been discussed in chapter 2.5

“Deficiencies”.

The procedure is as follows: For example, in case of a deficiency letter from the EC,

the contents of the deficiencies are added just at a glance, but the trial ID and the date

of the letter is given in a separate column to enable the identification of the respective

letter in the related trial folder. Additionally, the implementation of a corrective action, if

any, will be added to the text, e.g. an update of the participant information sheet.

Afterwards, an information e-mail will be sent to several parties: all trial teams, the

investigators, the quality control department, and the medical writers. The e-mail

summarizes the information given in the updated list and states where the new

information can be found.

6.6 ToDo-Client

Of main importance is the possibility to get a quick overview of all trial related

regulatory activities. This may be a simple excel sheet, where an operating program

could be inserted that helps to follow up on the timelines.

In our company, we have a more complex tool in place, where lots of information can

be displayed, and where nearly all relevant timelines can be tracked. Additionally,

substitution of the RAMs in case of holidays or illness is easier with this brief overview

of the trial progress.

Prior to submission of the application to BfArM and EC, there is only little information

given in the table: the EudraCT number, the name of principal investigator and project

manager (I have deleted those in the example, due to confidentiality), the type of the

trial (of importance for the calculating program duration of review periods), and the

information who will be responsible for the insurance coverage (this helps to prepare

the relevant documents, e.g. insurance notification form). Furthermore, the ticks in the

fields about the party executing the application – the sponsor or our regulatory

department – have influence on the alert function of the program. Consequently, there

will be no alert for the notification of the end of a trial to BfArM, when the sponsor is

responsible for that communication.


Figure 34: Screenshot of the ToDo Client for an exemplarily trial

When adding the trial code to the section “Filter” at the bottom of the page, the

respective trial will be loaded into the form, and all inserted information will be shown.

The column on the right side, titled “Alte Daten” (Old data) is a relict of a former

functionality, shows only data for older trials, and should therefore not be considered.

When adding the date to “Einreichungsdatum” (Date of submission) the date for

“Votum erwartet” (Vote expected) will automatically be calculated according to the

review period [as indicated through the ticks to “Art der Studie” (Type of the trial)], and

displayed in the respective field. If there were formal or contentual deficiencies, the




date for “Votum erwartet” will be updated by inserting further dates into the fields

“Beginn Bearbeitungsfrist” (Start of review period) and/or “Wieder rausgeschickt am”

(Resent on). In the end, the date of the final opinion/approval of the EC and BfArM,

respectively, will be inserted, and indicated if positive by ticking “pos. Votum”

(Approval).

The date of “FPFV = First participant – first visit” should be specified to have an

overview on the duration of a trial (annual safety report!) and the date of “LPLV = Last

participant – last visit” will be important for the notifications of the end of the trial (90

days!, if not a premature termination).

Of great importance is the alerting function of the program. On the left side, small

windows give the possibility to reveal the trials, where a notification of the end of the

trial, or the trial report (CTR) will be due in the next days. These trial IDs appear

automatically, if a fixed limit is exceeded. For example, for the CTR this limit is 30

days – the project team will then be reminded by my colleague or me to ask the

sponsor, whether the report is in advanced preparation, or maybe has already been

finalised. When the deadlines have expired, the trial ID will be shown in red letters.

After the trial ID has popped up, only a tick in the release box, or the insertion of a

specific date will delete that trial ID form the alert window. So in the case of the CTR,

filling in the date when the CTR has been sent to EC and/or BfArM will delete the

respective trial ID from the window “Zeige alle Studien, bei denen ein Jahresreport in

den nächsten … Tagen fällig ist” (Show all trial IDs, for which a CTR will be due in the

next … days).

The window “Amendments” has less functionality because these timelines are easier

to track, deficiencies are rare, and the calculating function will mainly help to have an

overview by when the votes should be received. The tick field for “Anzeige Insp./RP”

(Notification to Inspectorate/RP) serves as a reminding tool for the regulatory affairs

department not to forget about this duty. As you can see in the example below, the

last amendment has not yet been announced to the local authorities, because the trial

has already ended and the amendment will be notified to the authorities together with

the end of trial notification (this procedure is also inserted in the text field

“Kommentar”.



“Kommentar” (Comment) is a free text field, where relevant information may be

inserted. This is of help, if any “unusual” procedure should be noted, what otherwise

may cause confusion without this clarification – when dealing with lots of trials, it is

sometimes hard to remember what happened a few months ago in one of them.

A further helpful function is “Statistik” (Statistics), where all trials can be sorted by

several criteria, e.g. EudraCT number, date of submission, start of the trial and some

more.

From the column “Mängel” (Deficiencies) you can see, that contentual deficiency

letters “I” (i.e. inhaltlich = contentual) from BfArM are rare, whereas the EC sends

them nearly regularly. As already pointed out in section 2.5.1 “Deficiencies”, four trials

submitted in February 2010 were the only ones with formal deficiencies “F” regarding

the EC submission. BfArM applications have been submitted without formal

deficiencies throughout the year.

Figure 35: Screenshot of the trial statistics from 01 January to 29 December 2010



6.7 Miscellaneous

If you would have to deal with several members states in case of a multinational trial,

the report of the European Forum for Good Clinical Practice [13] may be of great help.

It summarizes the main requirements of the European Member States regarding

applications of clinical trials to ECs and CAs.

A further source of information may be the database of the Neuromuscular Network,

the “Treat-NMD Regulatory Affairs Database”, published by the University Medical

Center Freiburg (Universitätsklinikum Freiburg). The database contains of contact

details, national legislation, and other documents of several EU MS and aims to give

“advice to people who are involved in the planning of mono- or multi-centre clinical

trials within different European countries”. [40] The section “News” provides new or

updated information about different topics in the field of clinical trials.

For worldwide clinical trials, the “International Compilation of Human Research

Protections” lists more than “1,000 laws, regulations, and guidelines that govern

human subjects research in 101 countries, as well as the standards from a number of

international and regional organizations. … Its purpose is to help these groups

familiarize themselves with the laws, regulations, and guidelines where the research

will be conducted, to assure these standards are followed appropriately.” [31]



7 Conclusion and Outlook

From all the information stated above, it is easy to understand that from the

perspective of a regulatory affairs department filing a clinical trial application, fulfilling

subsequent duties in the course of the trial, and adhering to all relevant timelines is

not only printing some documents received from the sponsor, and putting them in

folders, but it is an active process which needs communication between all involved

parties. The input from the regulatory affairs department can only be given, when

there is a lot of experience in place, and all chances have been used to update the

expertise, be it from work or further training on a regular basis.

To have all relevant timelines in mind, well-structed working procedures are obligatory

and if such structures are also used through the other involved parties, the final

outcome will be better, and working will be facilitated.

As one example, it would be easier for sponsors and applicants, if all ECs in Germany

could agree on standardisation of their procedures so that no scope of discretion and

grounds for ongoing discussion to relevant issues (e.g. the procedure in connection

with amendments) between the regulatory departments of CROs and the sponsors will

remain. Some sponsors are hardly to convince that for the Ethics Committee of the

Medical Association North Rhine a review period of 20 days, as given in § 10 GCP

Ordinance [41], is mandatory and that submission of non-substantial amendments will

be rejected because it seems to be common practice of several ECs to accept

documents “for your attention” and to confirm receipt of those documents at very short

notice. Most likely, no thorough review would have been performed in such a short

time frame and it remains debatable, if the sponsor could rely on the legal reliability of

such confirmations of receipt in case of doubt.

The same is true for all documents handed out to the trial participants. The Ethics

Committee of the Medical Association North Rhine will only review them, apart from

the initial application, in connection with a substantial amendment, whereas the EC

Working Group always requests those documents after changes, even if not

substantial, as stated in Resolution 4: “Der Arbeitskreis der Ethik-Kommissionen fordert

immer die Vorlage folgender nichtbewertungspflichtiger nachträglicher Änderungen an:



Änderungen in Unterlagen, die sich an die Studienteilnehmer richten

(Informationsschriften, Fragebogen, etc.).” [38]

There is also an ongoing discussion whether an accident insurance will be required

through the wording in § 40(1)3 German Drug Law [22]: „8. ...für den Fall, dass bei der

Durchführung der klinischen Prüfung ein Mensch getötet oder der Körper oder die

Gesundheit eines Menschen verletzt wird, eine Versicherung nach Maßgabe des

Absatzes 3 besteht, die auch Leistungen gewährt, wenn kein anderer für den Schaden

haftet,...“ and § 40(3)2 German Drug Law [22]: „Ihr Umfang muss in einem

angemessenen Verhältnis zu den mit der klinischen Prüfung verbundenen Risiken

stehen und auf der Grundlage der Risikoabschätzung so festgelegt werden, dass für

jeden Fall des Todes oder der dauernden Erwerbsunfähigkeit einer von der klinischen

Prüfung betroffenen Person mindestens 500 000 Euro zur Verfügung stehen."

The wording has been interpreted by at least one member of the Ethics Committee of

the Medical Association North Rhine as if also accidents on the way to the trial site

must be insured by at least 500,000 EUR, but other EC members of that very EC and

also other ECs in Germany have a different opinion. Due to these differences, it might

be harder to perform further clinical trials in the responsibility of an EC that is not part

of the EC Working Group where only a recommendation for an accident insurance can

be found as a result of the 21. Jahresversammlung am 21./22. November 2003 (21st

annual assembly on 21/22 November 2003). [35] In the protocols of the following

years, the topic “Insurances” was discussed regularly, but by now no agreement is in

place that is borne by all German ECs. Consequently, the phrases of the respective

PIS/PIC template of the Ethics Committee of the Medical Association North Rhine

(Annex 7b) differ in this issue to those ones of the EC Working Group (Annex 7a). It

may be subject to another master thesis to compare the different templates of the

German ECs, because the Ethics Committee of the Medical Association North Rhine

is not nearly the only EC that is not a member of the EC Working Group, and it would

be interesting to learn why there are different versions in place although there is the

same regulatory basis.

For multinational trials, the Clinical Trials Facilitation Group (CTFG) is working on an

alignment of procedures in the different Member States. This working group is part of



the Heads of Medicines Agency, HMA; who agreed already in 2004 to establish this

department “to co ordinate implementaion of the EU clinical trials directive 2001/20 EC

across the member states” (HMA, URL: http://www.hma.eu/78.html, accessed on 19

January 2011). The activity report of the CTFG for the years 2008 and 2009 [5] gives

an overview about the already achieved proceedings. It would be more than helpful to

have such an alignment procedure between the Ethics Committees in Germany as

well, and also between the members of a single EC when assessing the submitted

documents of an applicant. Although having the EC Working Group in place, not only

the procedures of the different ECs are varying. There are several committee

members in one EC, and not all are part of each CTA assessment. So there are

preferences of single members that lead to different contentual deficiencies. For

example, we submitted several CTA applications with the same wording regarding the

informed consent procedure. The phrases were fine with the committees and we got

no deficiency letters to that issue. In contrast, in a very recent trial the responsible

committee requested to change the relevant wording considerably although parts of

the explanations were copied from their own PIS/PIC template.

In the end, an ongoing struggle remains to fulfil the differing requirements of only one

single EC, and in my opinion it will be inaccessible to come to a European adaption of

procedures when a national or even local adjustment is so hard to reach. A

commendable distinction refers to BfArM, where only slight differences between the

opinions of the responsible reviewers exist – apparently there are standard operating

procedures in place that simplify comparable procedures to ease the application

process for applicants and authority.

This is not meant as a complaint, because the role of the Ethics Committees cannot

be too highly praised within the procedures around clinical trials – the members of the

ECs are working on a voluntary basis and often have to review several trials in a short

time frame. The history has shown often enough the bad outcome of trials without a

thorough review of the planned activities by an EC (e.g. the thalidomide affair), and it

should be the main goal for all involved parties to perform clinical trials with a

minimized risk for the participants.

http://www.hma.eu/78.html



To facilitate the review process and to give the applicants clear advice on how to

create their documents, e.g. the PIS/PIC, it may be helpful to install a specific working

party with interested members from several ECs, and from regular applicants, such as

CROs. By having such a working group, more consistent opinions may possibly be

expressed in future votes, and particular topics such as the required wording of

specific sections of the submitted documents may be discussed face by face.

In general, a direct contact between applicant and members of the EC (or even with

the responsible chairperson) should be facilitated, similar to BfArM, where the

respective persons dealing with the case may be called directly, if necessary and

helpful.

For the list of already existing templates and guiding documents on the websites of the

ECs it should be clearly displayed when a document had been revised – maybe in a

section “News”. For example, recently I have found on an EC website the information

of the required number of copies in one document as tenfold and in another document

as 13-fold, and only a phone call could clarify, what really was needed.

An “electronic only” submission for at least those documents that could be read more

easily with the possibility to search expressions, and to jump to specific sections from

the table of contents (e.g. the protocol or the IB) would help to facilitate the application

process, and to spare loads of paper. Recently, we submitted a trial application with

three different IBs, one of them with more than 800 pages – the submission of these

files only on CD ROMs would have been of great help for us and probably also for the

members of the EC, and the responsible persons at BfArM. Of course, one condition

for this would be the technical equipment to read the CD ROMs.

Also of great help would be the possibility to amend a running application in case of

comments from either BfArM or EC to the other party. Mostly, the applications are

submitted in parallel, and deficiencies must be answered by amending the protocol.

Thus, it would simplify and shorten the whole process, if those requested changes

could be implemented into the documents sent to the other involved authority/EC

without initially waiting for their approval and sending an amendment later on.



8 Summary

Clinical trials are relevant parts of the development and for the marketing authorisation

of medicinal products, as well as after authorisation, to gain further knowledge about

the product. As of 4 April 2001, the basic principles for the conduct of clinical trials

were implemented through Directive 2001/20/EC of the European Parliament and of

the Council, the so-called “Clinical Trials Directive”. Through a profound risk

assessment of the results of preclinical investigations and previously conducted

clinical trials by the Ethics Committees and the relevant competent authorities of the

respective Member State, it should be guaranteed that the safety and well-being of the

trial participants, and the preservation of their very own data will be protected in every

respect.

Directive 2001/20/EC had been transferred into German law in August 2004 with the

12th amendment of the German Drug Law. Since then, a clinical trial must not be

conducted without having received a positive opinion of the responsible Ethics

Committee and an approval of the competent authority.

Neither the European directives nor the local implementations in Germany, GCP

Ordinance and German Drug Law, give detailed information about the format and

quantity of the documents that have to be submitted, and even in large pharmaceutical

companies, especially if situated in foreign countries, there is sometimes only poor

knowledge about the regulatory requirements of the application process and as well

during the conduct of a clinical trial in Germany.

Particulars to the application process, required documents, and the timelines may be

obtained through the websites of the relevant parties, e.g. either PEI or BfArM for the

competent authorities in Germany, the Central Authority of the Länder for Health

Protection with regard to Medicinal Products and Medical Devices for the local

authorities, and the EC Working Group, or their own websites, respectively, for the

Ethics Committees. Additionally, guidance documents, e.g. of the European

Community, may serve as road signs for what will be needed, but reality differs quite a

lot, especially when dealing with Ethics Committees (ECs). Despite any



recommendations, e.g. from the EC Working Group, each EC seems to have its own

way to deal with the submissions.

A “Best Practice Guide” as provided in this master thesis may help to find a way

through the regulatory jungle from the application procedure to the clinical trial report

in one single document – at least when conducting a mono-centre trial in North Rhine-

Westphalia, Germany.

Not only relevant documents are presented and their preparation is discussed, but

also timelines, formal requirements, and possible snares regarding the submission

package are highlighted.

Templates and drafts are of great help to facilitate recurring steps within the process

of application for an authorisation of a clinical trial – a variety of what is possible is

shown, and as well other measures to well-structured preparation of important

documents and timely adherence to relevant timelines are specified.



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http://www.gesetze-im-internet.de/gcp-v/index.html





http://www.gesetze-im-internet.de/amg-av/BJNR277500005.html



http://www.wma.net/en/30publications/10policies/b3/index.html













URL:http://www.wma.net/en/30publications/10policies/b3/index.html; accessed

on: 29 December 2010

44. World Health Organization. International Clinical Trials Registry Platform

(ICTRP). WHO Trial Registration Data Set (Version 1.2.1)

URL:http://www.who.int/ictrp/network/trds/en/index.html; accessed on: 29

December 2010


http://www.who.int/ictrp/network/trds/en/index.html





10 Appendices

Annex 1 Cover letter application_EC

Annex 2 Checklist application documents_EC

Annex 3 Section J_Checklist of information

Annex 4 Module 2_EC_German

Annex 5 Module 2_EC_English

Annex 6 German summary_Template

Annex 7a PIS_PIC template_German EC Working Group

Annex 7b PIS_PIC template_EC North Rhine

Annex 8 Confirmations of Investigators_Template

Annex 9 Authorisation letter_Template

Annex 10 Cover letter application_BfArM

Annex 11 Label for IMP_Template

Annex 12 ZLG form_Template

Annex 13 Substantial amendment notification form

Annex 14 Resolution 4_EC Working Group

Annex 15 Declaration end of trial form



Hiermit erkläre ich an Eides statt, die Arbeit selbständig verfasst und keine anderen als die angegebenen Hilfsmittel verwendet zu haben. ______________________ ______________________________ Datum Elke Gurschke


Appendices

Annex 1


Adresse der EK

Antrag auf zustimmende Bewertung einer klinischen Prüfung nach § 40 Abs. 1 Satz 2 AMG sowie § 7 GCP-V

Tagesdatum

EudraCT-Nr.:

Prüfplan-Code: Titel Sehr geehrte Damen und Herren, zur Beratung auf zustimmende Bewertung durch die Ethikkommission xxx machen wir zu oben genannter Studie folgende Angaben: Sponsor:

Vertreter in der EU: falls zutreffend

Antragsteller im Auftrag des Sponsors:

Prüfstelle:

Hauptprüfer:

Prüfer:

alle beteiligten Prüfer nennen Labor:

alle beteiligten Labors nennen Zur Beratung unseres Antrags senden wir Ihnen folgende Unterlagen in 9-facher Ausfertigung:

1. Anschreiben vom 2. Checkliste Antragsunterlagen vom 3. Modul 1 (CTA) vom mit Unterschriftsseite 4. Modul 2 vom 5. Erklärungen / Bestätigungen der Prüfer 6. Bestätigung der EudraCT-Nr. 7. Vollmacht des Sponsors 8. Material zur Rekrutierung 9. Vertrag mit dem Sponsor

Annex 1


a. Work Order b. Responsibility Split List

10. Deutsche Zusammenfassung des Prüfplans, Version vom 11. Prüfplan

a. Prüfplan, Version vom b. Unterschriften

12. Studienteilnehmerinformation / Einwilligungen a. Informationsbroschüre, Version vom mit Einwilligungserklärung, einschließlich

Einwilligungserklärung über die Speicherung personenbezogener Daten, Einwilligungserklärung zur Hepatitis B/C-Untersuchung und HIV-Test, Einverständniserklärung zusätzlicher Schwangerschaftstest bei Frauen, Einwilligungserklärung VIP-Check

b. Ergänzende Information und Einwilligung zur Teilnahme an der pharmakogenetischen Untersuchung, Version vom

c. Teilnehmerausweis d. Tagebuch Version vom

13. Investigator’s Brochure; Fachinformationen / SmPC a. Investigator’s Brochure Präparat, Edition vom b. Fachinformation Präparat, Stand c. Summary of Product Characteristics (SmPC) Präparat, Stand

14. Probandenversicherung a. Versicherungsbestätigung b. Versicherungspolice c. Allgemeine Versicherungsbedingungen d. Geschriebene Versicherungsbedingungen

15. Wegeunfallversicherung a. Versicherungsbestätigung b. Versicherungspolice c. Allgemeine Unfallversicherungsbedingungen d. Besondere Unfallversicherungsbedingungen

16. Lebensläufe / GCP-Zertifikate der Prüfärzte Hinweise zu den eingereichten Dokumenten:

• Da weder in der GCP-Verordnung noch im AMG die CRFs explizit als notwendige Einreichungsvoraussetzung genannt sind, werden diese Dokumente der Ethikkommission nicht zur Bewertung vorgelegt.

• Die Verhältnisse der Prüfstelle wurden zu Beginn des Jahres nach der Vorlage entsprechender Unterlagen als hinreichend bewertet. Es liegt uns hierzu die Bestätigung der Ethikkommission vor. Alle in dieser Prüfstelle tätigen Prüfärzte verfügen über die entsprechende Ausnahmegenehmigung der Ärztekammer Nordrhein, sind der Ethikkommission vor Aufnahme der Tätigkeiten für die betreffenden Studien gemeldet und von dieser zustimmend bewertet worden.

• Laut den Allgemeinen Versicherungsbedingungen, Abschnitt 1.5 „Zeitliche Geltung“ zum Versicherungsvertrag, die wir in der Anlage beifügen, besteht Versicherungsschutz für die gesamte Laufzeit der Studie, unabhängig von der Laufzeit des jeweiligen Versicherungsjahres.

• Eine Unfallversicherung ist für diese Studie nicht vorgesehen. Die in Papierform eingereichten Dokumente erhalten Sie gleichzeitig in elektronischer Form im xml- und pdf-Format auf CD-ROM. Wir bestätigen, dass beide Versionen identisch sind. Für Rückfragen stehen wir Ihnen jederzeit gerne zur Verfügung. Mit freundlichen Grüßen Name

Regulatory Affairs Manager

Annex 2 Best Practice Guide for Regulatory Affairs in a German CRO

ÖFFENTLICH-RECHTLICHE

ETHIK-KOMMISSIONEN IN DEUTSCHLAND

Anlage 3

Version 04.06.2005 1

EudraCT-Nr.:

CChheecckklliissttee:: EErrffoorrddeerrlliicchhee AAnnttrraaggssuunntteerrllaaggeenn ffüürr SSttuuddiieenn nnaacchh AAMMGG Die Punkte entsprechen der 12. AMG-Novelle und der GCP-V § 7 Abs. 2 (S. 1 der Checkliste) u. Abs. 3 (S. 2 der Checkliste).

EK (Die Kästchen in der 1. Spalte bitte nicht ausfüllen, werden von Ethik-Kommission ausgefüllt) Antragsteller (Alle Kästchen in der 2. oder 3. Spalte bitte ausfüllen – per Mausklick: z für zutreffend; nz für nicht zutreffend, immer

mit kurzer Erläuterung)

Anmerkung: Bitte immer Versionsnummer und –datum angeben (siehe schraffierte Fläche). Sofern keine einzelnen

Dokumente beigefügt sind, sondern die Informationen in anderen Dokumenten enthalten sind, bitte das Dokument

sowie Kapitel- oder Seitenzahl angeben. Bei Anlagen immer die Anlagen-Nummer angeben.

z nz

1. Kopie des Bestätigungsschreibens für die von der Europäischen Datenbank vergebene EudraCT-Nummer des Prüfplans (Anlage 6)

2. vom Sponsor oder seinem Vertreter unterzeichnetes Begleitschreiben in deutscher Sprache, das die EudraCT-Nummer, den Prüfplancode des Sponsors und den Titel der klinischen Prüfung angibt, Besonderheiten der klinischen Prüfung hervorhebt und auf die Fundstellen der diesbezüglichen Informationen in den weiteren Unterlagen verweist (Anlage 1; Begleitschreiben enthält Angaben zu Versionsnummern und/oder -daten der Anlagen)

3. vom Hauptprüfer oder vom Leiter der klinischen Prüfung sowie vom Sponsor oder seinem Vertreter unterzeichneter Prüfplan unter Angabe des vollständigen Titels und des Arbeitstitels der klinischen Prüfung, der EudraCT-Nummer, des Prüfplancodes des Sponsors, der Fassung und des Datums (Anlage 11)

4. Name oder Firma und Anschrift des Sponsors und, sofern vorhanden, seines in der Europäischen Union oder in einem Vertragsstaat des Abkommens über den Europäischen Wirtschaftsraum niedergelassenen Vertreters (Anlage 1)

5. Namen und Anschriften der Einrichtungen, die als Prüfstelle oder Prüflabor in die klinische Prüfung eingebunden sind, sowie der Hauptprüfer und des Leiters der klinischen Prüfung (Anlage 1)

6. Angabe der Berufe von Prüfern, die nicht Arzt sind, der wissenschaftlichen Anforderungen des jeweiligen Berufs und der seine Ausübung voraussetzenden Erfahrungen in der Patientenbetreuung sowie Darlegung, dass der jeweilige Beruf für die Durchführung von Forschungen am Menschen qualifiziert und Darlegung der besonderen Gegebenheiten der klinischen Prüfung, die die Prüfertätigkeit eines Angehörigen des jeweiligen Berufs rechtfertigen (Begründung s. Anlage 4, Abs. 12)

7. Prüferinformation (Investigator’s Brochure oder Fachinformation) (Anlage 13)

8. Bezeichnung und Charakterisierung der Prüfpräparate und ihrer Wirkstoffe (Anlage 10, Abs. 18)

9. Gegenstand der klinischen Prüfung und ihre Ziele (Anlage 10, Abs. 1-2)

10. Anzahl, Alter und Geschlecht der betroffenen Personen (Anlage 10, Abs. 13)

11. Erläuterung der Kriterien für die Auswahl der betroffenen Personen sowie der hierzu zugrundegelegten statistischen Erwägungen (samt Rekrutierungsmaßnahmen) (s. Anlage 4, Abs. 20; Anlage 8)

12. Begründung dafür, dass die gewählte Geschlechterverteilung in der Gruppe der betroffenen Personen zur Feststellung möglicher geschlechtsspezifischer Unterschiede bei der Wirksamkeit oder Unbedenklichkeit des geprüften Arzneimittels angemessen ist (Anlage 10, Abs. 13)

13. Plan für eine Weiterbehandlung und medizinische Betreuung der betroffenen Personen nach dem Ende der klinischen Prüfung (Anlage 10, Abs. 15)

14. mit Gründen versehene Angaben ablehnender Bewertungen der zuständigen Ethik-Kommissionen anderer Mitgliedstaaten der Europäischen Union oder anderer Vertragsstaaten des Abkommens über den Europäischen Wirtschaftsraum sowie Versagungen beantragter Genehmigungen durch die zuständigen Behörden anderer Mitgliedstaaten der Europäischen Union oder anderer Vertragsstaaten des Abkommens über den Europäischen Wirtschaftsraum; sollten zustimmende Bewertungen einer Ethik-Kommission oder eine Genehmigung durch eine zuständige Behörde mit Auflagen versehen worden sein, sind diese anzugeben




Version 04.06.2005 2

15. die Bestätigung, dass betroffene Personen über die Weitergabe ihrer pseudonymisierten Daten im Rahmen der Dokumentations- und Mitteilungspflichten nach § 12 und § 13 an die dort genannten Empfänger aufgeklärt werden; diese muss eine Erklärung enthalten, dass betroffene Personen, die der Weitergabe nicht zustimmen, nicht in die klinische Prüfung eingeschlossen werden (Anlage 5)

EudraCT-Nr.:

DDeerr EEtthhiikk--KKoommmmiissssiioonn ssiinndd ffeerrnneerr vvoorrzzuulleeggeenn (Fortsetzung der Checkliste): EK Antragsteller

z nz

1. Erläuterung der Bedeutung der klinischen Prüfung (Anlage 10, Abs. 4)

2. Bewertung und Abwägung der vorhersehbaren Risiken und Nachteile der klinischen Prüfung gegenüber dem erwarteten Nutzen für die betroffenen Personen und zukünftig erkrankte Personen (Anlage 10, Abs. 7)

3. Rechtfertigung für die Einbeziehung von Personen nach § 40 Abs. 4 und § 41 Abs. 2 und 3 des Arzneimittelgesetzes in die klinische Prüfung (trifft nicht zu, s. Anlage 4, Abs. 7)

4. Erklärung zur Einbeziehung möglicherweise vom Sponsor oder Prüfer abhängiger Personen (Anlage 5)

5. Angaben zur Finanzierung der klinischen Prüfung (Anlage 4, Abs. 24; Anlage 9)

6. Lebensläufe der Prüfer oder andere geeignete Qualifikationshinweise (Anlage 16)

7. Angaben zu möglichen wirtschaftlichen und anderen Interessen der Prüfer im Zusammenhang mit den Prüfpräparaten (Anlage 5)

8. Angaben zur Eignung der Prüfstelle, insbesondere zur Angemessenheit der dort vorhandenen Mittel und Einrichtungen sowie des zur Durchführung der klinischen Prüfung zur Verfügung stehenden Personals und zu Erfahrungen in der Durchführung ähnlicher klinischer Prüfungen (liegen bereits vor; s. Anschreiben)

9. Informationen und Unterlagen, die die betroffenen Personen erhalten, in deutscher Sprache, sowie eine Darstellung des Verfahrens der Einwilligung nach Aufklärung (Anlage 12)

10. Beschreibung der vorgesehenen Untersuchungsmethoden und eventuelle Abweichungen von den in der medizinischen Praxis üblichen Untersuchungen (s. Anlage 4, Abs. 10)

11. Beschreibung der vorgesehenen Verfahrensweise, mit der verhindert werden soll, dass betroffene Personen gleichzeitig an anderen klinischen Prüfungen oder Forschungsprojekten teilnehmen oder vor Ablauf einer erforderlichen Karenzzeit an der klinischen Prüfung teilnehmen (Anlage 4, Abs. 15)

12. Beschreibung, wie der Gesundheitszustand gesunder betroffener Personen dokumentiert werden soll (Anlage 4, Abs. 16)

13. Nachweis einer Versicherung nach § 40 Abs. 1 Nr. 8 und Abs. 3 des Arzneimittelgesetzes (Versicherungspolice und –bedingungen) (Anlage 14)

14. hinsichtlich der Vergütung der Prüfer und der Entschädigung der betroffenen Personen getroffene Vereinbarungen (Anlage 4, Abs. 21)

15. Erklärung zur Einhaltung des Datenschutzes (Anlage 5)

16. alle wesentlichen Elemente der zwischen dem Sponsor und der Prüfstelle vorgesehenen Verträge (Anlage 9)

17. Kriterien für das Aussetzen oder die vorzeitige Beendigung der klinischen Prüfung (s. Anlage 4, Abs. 22)

18. bei multizentrischen klinischen Prüfungen, die im Geltungsbereich des Arzneimittelgesetzes in mehr als einer Prüfstelle erfolgen, eine Liste der Bezeichnungen und Anschriften der beteiligten Ethik-Kommissionen

19. eine Zusammenfassung der wesentlichen Inhalte des Prüfplans in deutscher Sprache, wenn der Prüfplan nach Absatz 2 Nr. 3 in englischer Sprache vorgelegt wird (Anlage 10)




Version 04.06.2005 3

DDaarrüübbeerr hhiinnaauuss lliieeggeenn ddeenn AAnnttrraaggssuunntteerrllaaggeenn bbeeii:: (Für multizentrische Studien bitte immer beilegen, für monozentrische Studien je nach Vorgabe der zuständigen Ethik-Kommission)

Modul 1, unterschrieben am

Modul 2, unterschrieben am

Verantwortlich für den Sponsor (Unterschrift/Datum): ..........................................................................................

Verantwortlich für die Ethik-Kommission (Unterschrift/Datum): ............................................................................


Section J Checklist – October 2005 1/1

Section J. (Formerly Section K) CHECK LIST OF INFORMATION

(Information that the concerned Member State’s Competent Authority and Ethics

Committees (CA & EC1) require according to the table in Attachment 1)

CA EC INFORMATION PROVIDED

1 General

1.1 Receipt of confirmation of EudraCT number

1.2 Covering letter

1.3 Application form

1.4 List of Competent Authorities within the Community to which the application has been submitted

and details of decisions

1.5 Copy of ethics committee opinion in the MS concerned when available

1.6 Copy/summary of any scientific advice

1.7 If the applicant is not the sponsor, a letter of authorisation enabling the applicant to act on behalf of

the sponsor

2 Subject related

2.1 Informed consent form

2.2 Subject information leaflet

2.3 Arrangements for recruitment of subjects

3 Protocol related

3.1 Clinical trial protocol with all current amendments

3.2 Summary of the protocol in the national language

3.3 Peer review of trial when available

3.4 Ethical assessment made by the principal/coordinating investigator, if not given in the application

form or protocol

4 IMP related

4.1 Investigator's brochure

4.2 Investigational Medicinal Product Dossier (IMPD)

4.3 Simplified IMPD for known products (see table 1)

4.4 Summary of Product Characteristics (SmPC) (for products with marketing authorisation in the

Community)

4.5 Outline of all active trials with the same IMP

4.6 If IMP manufactured in E.U. and if no marketing authorisation in EU:

4.6.1 Copy of the manufacturing authorization referred to in Art. 13.1. of the Directive stating the scope

of this authorization

4.7 If IMP not manufactured in E.U. and if no marketing authorisation in EU:

4.7.1 Certification of the QP that the manufacturing site works in compliance with GMP at least

equivalent to EU GMP, or that each production batch has undergone all relevant analyses, tests or

checks necessary to confirm its quality

4.7.2 Certification of GMP status of active biological substance

4.7.3 Copy of the importers manufacturing authorization referred to in Art. 13.1. of the Directive stating

the scope of this authorization

4.8 Certificate of analysis for test product in exceptional cases :

4.8.1 Where impurities are not justified by the specification or when unexpected impurities (not covered

by specification) are detected

4.9 Viral safety studies when applicable.

1 Tick all boxes to show information provided to the ethics committee concerned (EC) and the competent authority (CA).


Section J Checklist – October 2005 2/2

CA EC INFORMATION PROVIDED

4.10 Applicable authorisations to cover trials or products with special characteristics (if available) e.g.

GMOs, radiopharmaceuticals

4.11 TSE Certificate when applicable

4.12 Examples of the label in the national language

5 Facilities & staff related

5.1 Facilities for the trial

5.2 CV of the coordinating investigator in the MS concerned (for multicentre trials)

5.3 CV of each investigator responsible for the conduct of a trial in a site in the MS concerned

(principal investigator)

5.4 Information about supporting staff

6 Finance related

6.1 Provision for indemnity or compensation in the event of injury or death attributable to the clinical

trial

6.2 Any insurance or indemnity to cover the liability of the sponsor or investigator

6.3 Compensation to investigators

6.4 Compensation to subjects

6.5 Agreement between the sponsor and the trial site

6.6 Agreement between the investigators and the trial sites

6.7 Certificate of agreement between sponsor and investigator when not in the protocol


1

Modul 2

Arbeitskreis Medizinischer Ethik-Kommissionen

1. EudraCT Studiennummer: Nummer

2. Titel der klinischen Prüfung

Deutscher Titel

Englischer Titel

3. Zusammenfassung der klinischen Prüfung

§ 7 Abs. 2 Nr. 9 GCP-V

Siehe Anlage 10 (Deutsche Zusammenfassung des Prüfplans)

oder

Siehe Anlage 11 (Prüfplan), Abschnitt x: Summary o.ä.

4. Ergebnisse von präklinischen Untersuchungen oder Begründung für den Verzicht auf präklinische Tests

Siehe Anlage 10 (Deutsche Zusammenfassung), Abschnitt 19: Ergebnisse einer dem jeweiligen Stand der wissenschaftlichen Erkenntnis entsprechenden pharmakologisch-toxikologischen Prüfung

§ 40 Abs. 1 Nr. 7 AMG

Wir bestätigen hiermit, dass alle Prüfärzte entsprechend § 40 Abs. 1 Nr. 7 AMG über die pharmakologisch-toxikologischen Ergebnisse und die voraussichtlich mit der klinischen Prüfung verbundenen Risiken durch einen verantwortlichen Wissenschaftler informiert werden. Entsprechende Erklärungen und Bestätigungen aller Prüfer sind dem Antrag als Anlage 5 beigefügt.

5. Primäre Hypothese und wenn relevant, auch sekundäre Hypothesen zu Durchführung der geplanten klinischen Prüfung


Siehe Anlage 10 (Deutsche Zusammenfassung), Abschnitt 2: Prüfziel(e)

6. Ethische Überlegungen zur geplanten klinischen Prüfung

§ 7 Abs. 3 Nr. 1 und 2

Siehe Anlage 10 (Deutsche Zusammenfassung), Abschnitt 7: Nutzen-Risiko-Abwägung

7. Gründe für den Einschluss von Personen aus besonders geschützten Gruppen


Es werden minderjährige bzw. nicht einwilligungsfähige Personen in die Prüfung einbezogen:

Nein

Ja Ausführungen zur Rechtfertigung der Einbeziehung der benannten Personenkreise

8. Beschreibung des Verfahrens zum Einschluss von Teilnehmern (alle zur Verwendung bestimmten Materialien müssen beigelegt werden)

§ 40 Abs. 1 AMG

Siehe Anlage 8 (Material zur Rekrutierung)

9. Vorgehen an der Prüfstelle zur Information und Erlangung der informierten Einwilligung der Studienteilnehmer, der Eltern oder des gesetzlichen Vertreters, wenn erforderlich


Alle Studienteilnehmer werden vor Beginn der klinischen Prüfung ausführlich (mündlich und schriftlich) über die Studie informiert. Die Aufklärung wird grundsätzlich von einem Arzt durchgeführt. Den Studienteilnehmern wird die Möglichkeit gegeben, ihre Teilnahme gründlich zu überdenken und


2

alle offenen Fragen zu klären. Die Einwilligung zur Teilnahme an der Studie erfolgt durch die Unterschrift des Studienteilnehmers auf der jeweiligen Einwilligungserklärung. Die Informationsbroschüre / Einwilligungserklärung wird jedem Studienteilnehmer zusammen mit den Versicherungsdokumenten ausgehändigt.

10. Studienbezogene Maßnahmen und alle erforderlichen Abweichungen von der üblichen Routine-Behandlung

Siehe Anlage 11 (Prüfplan), Abschnitt x: Methods and Assessments Study Procedures o.ä.

§ 7 Abs. 3 Nr. 10 GCP-V

Die Studie bedarf nach § 7 Abs. 3 Nr. 10 GCP-V einer Genehmigung durch das Bundesamt für Strahlenschutz

Nein

Ja

11. Risikoeinschätzung, vorhersehbare Risiken der Behandlung und sonstiger studienbedingter Verfahren, die eingesetzt werden sollen


Siehe Anlage 12 (Informationsbroschüre / Einwilligungserklärung), Abschnitt 2.2: Welche Risiken oder Unannehmlichkeiten sind mit der Teilnahme an der Studie verbunden?

12. Frühere Erfahrungen aus der Durchführung ähnlicher klinischer Prüfungen an der Prüfstelle


Die sachlichen, personellen und organisatorischen Anforderungen für die Durchführung der klinischen Prüfung sind gewährleistet. Die Betreuung der Studienteilnehmer durch qualifiziertes Personal wird sichergestellt, es liegen umfangreiche Erfahrungen in der Durchführung klinischer Studien vor. Es nehmen keine nichtärztlichen Prüfer an der Studie teil.

Mit Schreiben vom ttmmjjjj wurde von der Ethikkommission xxx die Überprüfung der lokalen Verhältnisse der Prüfstelle xxx für das laufende Jahr bestätigt. Alle in dieser Prüfstelle tätigen Prüfärzte verfügen über die entsprechende Ausnahmegenehmigung der Ärztekammer xxx, sind der Ethikkommission vor Aufnahme der Tätigkeiten für die betreffenden Studien gemeldet und von dieser zustimmend bewertet worden.

Für die weiteren beteiligten Prüfstellen werden in der Anlage 17 (Eignung der Prüfstellen), entsprechende Dokumentationen vorgelegt. Nur bei Multicenterstudien oder weiteren beteiligten Prüfern (z.B. Radiologe)

Die aktuellen Lebensläufe und GCP Zertifikate aller Prüfer sind als Anlage 16 beigefügt.

13. Alle voraussichtlichen Vorteile für die in die klinische Prüfung einbezogenen Personen


Siehe Anlage 12 (Informationsbroschüre / Einwilligungserklärung), Abschnitt 2.1: Welchen persönlichen Nutzen habe ich von der Teilnahme an der Studie?

14. Abhängigkeit zwischen Studienteilnehmer und Prüfer/Sponsor


Vom Sponsor oder Prüfer abhängige Personen werden nicht in die klinische Studie eingeschlossen. Entsprechende Erklärungen und Bestätigungen aller Prüfer sind dem Antrag als Anlage 5 beigefügt.

15. Verfahren an der Prüfstelle zur Feststellung, ob der Studienteilnehmer gleichzeitig an anderen Forschungsprojekten beteiligt ist, oder ob eine vorgegebene Zeitspanne seit der letzten Teilnahme an einem Projekt verstrichen ist

§ 7 Abs. 3 Nr. 11 GCP-V

Die Prüfstelle xxx nimmt an dem zentralen Probanden-Meldesystem VIP Check international teil. VIP Check international ist eine Datenbank, in der im Interesse der Sicherheit bei der Arzneimittelentwicklung und zum (Selbst-) Schutz der Probanden, Kenndaten von Personen, die an


3

klinischen Studien teilnehmen, erfasst werden.

Folgende Kenndaten werden aus Personalausweis oder Reisepass in verschlüsselter Form vor Ort gespeichert und an das zentrale Probanden-Meldesystem VIP Check international nach Freiburg gemeldet: Vorname, Nachname, Geburtsort, Geburtstag, Geschlecht, Nationalität sowie Daten zur Studie: Studien-Nummer, Beginn und Ende der Studie, Sperrfrist (bis zu 90 Tage). Das Probanden-Meldesystem in Freiburg wird treuhänderisch und vertraulich von VIP Check international verwaltet.

Das Konzept sowie die Probanden-Datenbank wurden von Datenschutzbeauftragten des baden-württembergischen Innenministeriums besichtigt und bewilligt. Zugang zur Probanden-Datenbank haben nur registrierte Teilnehmer, die klinische Studien mit Probanden durchführen. Bei Multicenterstudien entsprechend abklären und anpassen

16. Maßnahmen und Methoden zur Aufzeichnung der Gesundheitskontrollen von gesunden Studienteilnehmern

§ 7 Abs. 3 Nr. 12 GCP-V

Vor Einschluss der Studienteilnehmer in die Studie wird im Rahmen der Aufnahmeuntersuchung eine Anamnese, eine ärztliche Untersuchung u.a. mit Messung der Vitalwerte und Laboruntersuchungen durchgeführt. Alle diesbezüglichen Angaben und Werte werden in den Teilnehmerakten und gegebenenfalls in der studienspezifischen Dokumentation aufgezeichnet. nur bei gesunden Probanden, ansonsten nicht zutreffend auch in Checkliste anpassen Teil 2, Punkt 12

17. Methoden, um unerwünschte Ereignisse zu erkennen, sie aufzuzeichnen und zu berichten; Berichterstattung unerwünschter Ereignisse (Beschreibung, wann, von wem und wie dieses erkannt wurde, z.B. durch Befragung oder an Hand von Listen)

Siehe Anlage 11 (Prüfplan), Abschnitt x: Adverse Events and Pregnancies Subject Safety o.ä.

18. Vorgesehene Maßnahmen zum Schutze der erhobenen personenbezogenen Daten, Originalbefunde und Körperproben

§ 7 Abs. 3 Nr. 15 GCP-V

Durch Pseudonymisierung der Daten wird sichergestellt, dass die personenbezogenen Angaben geschützt bleiben. Beim Umgang mit personenbezogenen Daten werden die Grundsätze des Datenschutzrechtes beachtet. Entsprechende Erklärungen und Bestätigungen aller Prüfer sind dem Antrag als Anlage 5 beigefügt.

§ 40 Abs. 2a AMG sowie § 7 Abs. 2 Nr. 15 GCP-V

Die Studienteilnehmer werden über die Weitergabe ihrer pseudonymisierten Daten aufgeklärt. Studienteilnehmer, die einer Weitergabe der Daten nicht zustimmen, werden nicht in die Studie eingeschlossen. Entsprechende Erklärungen und Bestätigungen aller Prüfer sind dem Antrag als Anlage 5 beigefügt.

19. Plan zur Behandlung oder Versorgung, nachdem der Studienteilnehmer aus der Studie ausgeschieden ist

§ 7 Abs. 2 Nr. 13 GCP-V

Siehe Anlage 10 (Deutsche Zusammenfassung), Abschnitt 15: Plan für eine Weiterbehandlung und medizinische Betreuung der Studienteilnehmer nach dem Ende der klinischen Prüfung

20. Statistische Erwägungen und Gründe für die Anzahl der in die klinische Prüfung einzubeziehenden Teilnehmer

§ 7 Abs. 2 Nr. 11 und 12 GCP-V

Siehe Anlage 10 (Deutsche Zusammenfassung), Abschnitt 12: Studienteilnehmer, Geschlechterverteilung, geschlechtsspezifische Unterschiede und zugrunde gelegte statistische Kriterien

21. Betrag und Verfahren zur Bezahlung oder zur Entschädigung der Studienteilnehmer

§ 7 Abs. 3 Nr. 14 GCP-V

Die von den Prüfzentren/Prüfern im Rahmen der Studiendurchführung erbrachten Leistungen werden durch den Sponsor vergütet.


4

Die Studienteilnehmer erhalten eine Aufwandsentschädigung:

nein

ja, in Höhe von: EUR 0000

Bei vorzeitiger Beendigung der Studienteilnahme kann eine angemessene Aufwandsentschädigung ermittelt werden. Die Auszahlung der Aufwandsentschädigung erfolgt bargeldlos und nur gegen Bekanntgabe der Kontonummer eines Kreditinstitutes. Die Aufwandsentschädigung unterliegt einem Abtretungsverbot.

22. Regelung für den Abbruch (bei einer Person) oder zur vorzeitigen Beendigung des Versuchs an der Prüfstelle / den Prüfstellen in einem bestimmten Mitgliedsstaat oder im Ganzen

§ 7 Abs. 3 Nr. 17 GCP-V

Siehe Anlage 11 (Prüfplan), Abschnitt x: Premature Termination of the Trial/Trial Site o.ä.

23. Vereinbarungen über den Zugriff des/der Prüfer(s) auf Daten, Publikationsrichtlinien, etc.

Siehe Anlage 11 (Prüfplan), Abschnitt x: Reports and Publications o.ä.

oder

Siehe Anlage 9 (Vertrag), Abschnitt x: XXX

24. Finanzierung (wenn nicht im Protokoll angegeben) und Informationen über finanzielle oder andere Interessen der / des Prüfer(s)

§ 7 Abs. 3 Nr. 5 und 7 GCP-V

Die Finanzierung erfolgt durch den Sponsor. Die öffentlichen Kassen und sonstige Leistungsträger werden nicht mit den Kosten der Studie und deren unmittelbaren Folgen belastet. Der Vertrag ist den Unterlagen als Anlage 9 beigefügt.

Von Seiten der Prüfer bestehen keine wirtschaftlichen und anderen Interessen im Zusammenhang mit den Prüfpräparaten. Entsprechende Erklärungen und Bestätigungen aller Prüfer sind dem Antrag als Anlage 5 beigefügt.

NAME UND UNTERSCHRIFT DES ANTRAGSTELLERS (im Auftrag des Sponsors)

Ich bestätige hiermit, dass die in diesem Antrag angegebenen Informationen zutreffen und ich der Überzeugung bin, dass die klinische Prüfung in Übereinstimmung mit dem Protokoll sowie landesrechtlichen Bestimmungen und den Vorgaben von "Good Clinical Practice" durchgeführt werden kann.

Vorname:

Name:

Adresse:

Position: Regulatory Affairs Manager

Datum: Unterschrift:

Anmerkung:

Durch die angemessene Bearbeitung von Modul 2 und Einreichung von Modul 1 liegen

zu folgenden 20 Punkten aus der GCP-V Angaben vor:

Modul 2: § 7 Abs. 2: Nr. 9, 11, 12, 13, 15

§ 7 Abs. 3: Nr. 1-5, 9-12, 14, 15, 17

Modul 1: § 7 Abs. 2: Nr. 8, 10, 14


28

Attachment 4

Information on the application form for the Ethics Committee

Module 1

This first module of the application form to be used to the Ethics Committee is the same as

the form used in the submission to the competent authority.

To be found in ‘Detailed guidance for the request for authorisation of a clinical trial on a

medicinal product for human use to the competent authorities, notification of substantial

amendments and declaration of the end of the trial’ Annex 1.

Module 2

Module 2 is optional and represents a national or local Ethics Committee application form.

This second module can contain headings that might be helpful for the ethical review by the

Ethics Committee. The aim of the example given in this section is to provide guidance on how

trial and site specific information might be presented to present the ethical issues and describe

the trial in lay language. The list of items addressed is not complete and can be modified

according to the responsibilities assigned to the Ethics Committee in the Member State.

1. EudraCT trial number

Ethics Committee trial ID

2. Title of the project (understandable for lay persons)

3. Summary of the project. (justification and relevance)

4. Results of pre-clinical tests or reasons for not doing pre-clinical tests

5. Primary hypothesis in this trial (if relevant, also secondary hypotheses)

6. Research ethical considerations

(Identify and state any possible problems that might occur. Present possible gain in

knowledge to be obtained in the trial and its importance, possible risks for injuries or

distress for the participants. Present your own evaluation of the risk-benefit ratio).

7. Reason for including persons from vulnerable groups, i.e. minors, temporarily or

permanently incapacitated subjects.

8. Description of the recruitment procedure (all material to be used should be appended)

9. Procedure at the site to provide information and obtain consent from the subjects, or

parents or legal representatives if applicable (who will give the information and when,

need for legal representatives, witness etc).

10. Investigational procedures and any deviations necessary from the routine treatment

11. Risk assessment, foreseeable risks of treatment and procedures to be used (incl. pain,

discomfort, violation of integrity and means to avoid and/or take care of unforeseen /

unwanted events)

12. Previous experience of the conduct of similar research procedures at this site.


29

13. Any foreseeable benefit for included subjects

14. Relation between subject and investigator (patient-physician, student – teacher etc)

15. Procedures of the site to check if the subject participates simultaneously in other

research or if a required period has elapsed since previous participation in research (of

special importance when healthy subjects are included in pharmacology trials).

16. Requirements and methods for recording health control for healthy subjects (i.e. hospital

files or other national requirements)

17. Methods for searching, recording and reporting adverse effects (describe when, by

whom and how, i.e. open questions and/or according to lists)

18. Procedures used to protect the privacy of recorded data, source documents and samples

(if applicable).

19. Plan for treatment or care after the subject has ended the participation in the trial (who

will be responsible and where)

20. Statistical consideration and reasons for the number of subjects to be included in the

trial.

21. Amount and procedure for remuneration or compensation of subjects (description of

amount paid during the participation in the trial and for what, i.e. travel cost, loss of

earning, pain and discomfort etc).

22. Rules for stopping or prematurely ending the trial at the site(s) in this Member State or

as a whole

23. Agreement on investigator’s access to data, publication policy etc. (if not available in

the protocol)

24. Sources of funding (if not available in the protocol) and information on financial or

other interests of the investigator(s).


30

NAME AND SIGNATURE OF APPLICANT - CO-ORDINATING

INVESTIGATOR/PRINCIPAL INVESTIGATOR (and/or sponsor, if applicable)

I hereby confirm that the information given in this application is correct and that I am of the

opinion that it will be possible to conduct the trial in accordance with the protocol, national

regulations and principles of Good Clinical Practice.

Name :

Surname :

Address :

Position: :

Date : Signature:


Deutsche Zusammenfassung des Prüfplans

Prüfplancode Erstelldatum

Interner Studiencode Status / Versions-Nr.

EudraCT-Nr. Seite 1 von 1


Prüfplan-Code

Titel






Inhaltsverzeichnis

Seite

1 Wissenschaftliche Kurzbeschreibung 3

2 Prüfziel(e) 3

3 Endpunkt(e) 3

4 Rationale der klinischen Prüfung 3

5 Einschlusskriterien 3

6 Ausschlusskriterien 3

7 Nutzen-Risiko-Abwägung 3

8 Hinweise auf Besonderheiten der klinischen Prüfung 4

9 Phase der Prüfung 4

10 Studiendesign 4

11 Art der Prüfung 4

12 Vorgesehene Dauer der Prüfung 4

13 Studienteilnehmer, Geschlechterverteilung, geschlechtsspezifische Unterschiede und zugrunde gelegte statistische Kriterien 4

14 Auswertkriterien, Zwischenauswertung 5

15 Plan für eine Weiterbehandlung und medizinische Betreuung der Studienteilnehmer nach dem Ende der klinischen Prüfung 5

16 Abbruchkriterien 5

17 Prüfpräparat(e) 5

18 Bezeichnung und Charakterisierung der Prüfpräparate und ihrer Wirkstoffe 5

19 Ergebnisse einer dem jeweiligen Stand der wissenschaftlichen Erkenntnis entsprechenden pharmakologisch-toxikologischen Prüfung 5

20 Vorprüfungen am Menschen 5






1 Wissenschaftliche Kurzbeschreibung

2 Prüfziel(e)

2.1 Primäres Prüfziel

2.2 Sekundäre Prüfziele

3 Endpunkt(e)

3.1 Primärer Endpunkt

3.2 Sekundäre Endpunkte

4 Rationale der klinischen Prüfung

Rechtfertigung und Relevanz

5 Einschlusskriterien

nur die wichtigsten Kriterien in Bullet points

6 Ausschlusskriterien

nur die wichtigsten Kriterien in Bullet points

7 Nutzen-Risiko-Abwägung

Gegenüberstellung und Bewertung vorhersehbarer Risiken und Nachteile (Nebenwirkungen und Belastungen) der klinischen Prüfung zu dem erwarteten Nutzen für Studienteilnehmer und zukünftig erkrankte Personen

Ethische Überlegungen zur geplanten klinischen Prüfung (alle möglicherweise auftretenden Probleme

möglicher Wissenszuwachs, der aus der klinischen Prüfung erhalten werden soll und seine Bedeutung

mögliche Risiken für Gesundheitsschäden, Beeinträchtigungen, Belastungen oder sonstige Nachteile der Studienteilnehmer






8 Hinweise auf Besonderheiten der klinischen Prüfung

möglichst mit Verweisen auf die Fundstelle in den Unterlagen (z.B. erstmalige Anwendung am Menschen, Anwendung bei einer speziellen Population von Patienten)

9 Phase der Prüfung

10 Studiendesign

offen blind doppelblind

vergleichend randomisiert cross-over placebokontrolliert

monozentrisch multizentrisch multinational

11 Art der Prüfung

Prophylaxe Diagnostik Therapie

Pharmakokinetik Pharmakodynamik Pharmakogenetik

Verträglichkeit Wirksamkeit Bioäquivalenz

Sonstige �

12 Vorgesehene Dauer der Prüfung

Insgesamt:

Beginn:

Ende:

13 Studienteilnehmer, Geschlechterverteilung, geschlechtsspezifische Unterschiede und zugrunde gelegte statistische Kriterien

Anzahl der Teilnehmer in der Prüfung insgesamt:

falls zutreffend davon Männer: / Frauen:

Begründung dafür, dass die gewählte Geschlechterverteilung in der Gruppe der Studienteilnehmer zur Feststellung möglicher geschlechtsspezifischer Unterschiede bei der Wirksamkeit oder Unbedenklichkeit des geprüften Arzneimittels angemessen ist

zugrunde gelegte statistische Überlegungen, insbesondere biometrische Methoden, spezielle statistische Auswertung und zu prüfende Hypothese

Angaben zur Erläuterung der Kriterien für die Auswahl der Studienteilnehmer und der zugrunde gelegten statistischen Erwägungen






14 Auswertkriterien, Zwischenauswertung

Auswertkriterien

Angaben, ob eine Zwischenauswertung vorgesehen ist

15 Plan für eine Weiterbehandlung und medizinische Betreuung der Studienteilnehmer nach dem Ende der klinischen Prüfung

Textbeispiel für gesunde Teilnehmer

Die Notwendigkeit einer spezifischen Behandlung wird im Regelfall nicht bestehen, da ausschließlich gesunde Studienteilnehmer eingeschlossen werden. Eine medizinische Betreuung über den Studienabschluss hinaus erfolgt gegebenenfalls bei einem vorzeitigen Studienabbruch aus medizinischen Gründen oder sofern das Auftreten unerwünschter Ereignisse dies erfordert.

16 Abbruchkriterien

Kriterien für das Aussetzen oder die vorzeitige Beendigung der klinischen Prüfung sowohl für den Einzelfall als auch für die gesamte Studie

17 Prüfpräparat(e)

falls mehrere Präparate angewendet werden, einzeln zuordnen

Neuentwicklung (ggf. Name)

zugelassen für die Indikation (ggf. Name) bei Anwendung außerhalb der Indikation

zugelassen für die vorgesehene Indikation und Anwendungsform (ggf. Name)

18 Bezeichnung und Charakterisierung der Prüfpräparate und ihrer Wirkstoffe

nur Prüfpräparate (IMPs) aufführen, keine non-IMPs

19 Ergebnisse einer dem jeweiligen Stand der wissenschaftlichen Erkenntnis entsprechenden pharmakologisch-toxikologischen Prüfung

20 Vorprüfungen am Menschen

Annex 7a Best Practice Guide for Regulatory Affairs in a German CRO

AMG-Probanden-Information und -Einwilligung EUDRACT-Nr. ........... Version ........... vom ...... Seite 1 von 11

MUSTERTEXT

für die Probanden-Information und -Einwilligung zur Durchführung einer klinischen Prüfung eines Arzneimittels

mit volljährigen einwilligungsfähigen Probanden1

empfohlen vom Arbeitskreis Medizinischer Ethik-Kommissionen gemäß Beschluss vom 14.6.2008

Alle kursiv gedruckten Textstellen enthalten Hinweise zum Erstellen

der Probanden-Information und -Einwilligung

Prüfstelle: ........... Angaben zur jeweiligen Prüfstelle mit Adresse und Telefonnummer Prüfarzt: ........... EUDRACT-Nr. ........... Diese gehört wie die Angabe der Version der Probanden-Information

auch in die fortlaufende Fußzeile

Titel der Studie deutsch, inklusive Prüfplancode

Sehr geehrte Dame, sehr geehrter Herr, wir möchten Sie fragen, ob Sie bereit sind, an der von uns vorgesehenen klinischen Prüfung (Studie) teilzunehmen. Klinische Prüfungen sind notwendig, um Erkenntnisse über die Wirksamkeit und Verträglichkeit von Arzneimitteln zu gewinnen oder zu erweitern. Deshalb schreibt der Gesetzgeber im Arzneimittelgesetz vor, dass neue Arzneimittel klinisch geprüft werden müssen. Die klinische Prüfung, die wir Ihnen hier vorstellen, wurde – wie es das Gesetz verlangt – von der zuständigen Ethikkommission zustimmend bewertet und von der zuständigen Behörde genehmigt. Diese klinische Prüfung wird in........... (Ort der

Durchführung)/an mehreren Orten durchgeführt; es sollen insgesamt ungefähr ........... Personen daran teilnehmen. Die Studie wird veranlasst, organisiert und finanziert durch ........... (Name, Sitz), den Sponsor dieser Studie. Ihre Teilnahme an dieser klinischen Prüfung ist freiwillig. Sie werden in diese Prüfung also nur dann einbezogen, wenn Sie dazu schriftlich Ihre Einwilligung erklären. Sofern Sie nicht an der klinischen Prüfung teilnehmen oder später aus ihr ausscheiden möchten, erwachsen Ihnen daraus keine Nachteile. Der Prüfarzt hat Ihnen bereits eine Reihe von Informationen zu der geplanten Studie gegeben. Der nachfolgende Text soll Ihnen die Ziele und den Ablauf erläutern. Anschließend wird ein Prüfarzt das Aufklärungsgespräch mit Ihnen führen. Bitte zögern Sie nicht, alle Punkte anzusprechen, die Ihnen unklar sind. Sie werden danach ausreichend Bedenkzeit erhalten, um über Ihre Teilnahme zu entscheiden.

1

Im Rahmen dieses Textes schließt die männliche Bezeichnung stets die weibliche Bezeichnung mit ein.



1. Warum wird diese Prüfung durchgeführt?

�� (Bezeichnung des Prüfpräparats) ist ein Arzneimittel in klinischer Erprobung und wird zur Behandlung von �� (Name der Erkrankung) entwickelt, d. h. es ist von der Behörde für die Behandlung dieser Krankheit noch nicht zugelassen (ggf. Hinweis auf bereits bestehende

Zulassungen für andere Indikationen). In der geplanten klinischen Prüfung wird �� (Bezeichnung des Prüfpräparats) zum ersten Mal (zum ersten Mal in der hier vorgesehenen Dosierung von …/zum ersten

Mal in der hier vorgesehenen Dauer von … Tagen/Wochen) am Menschen eingesetzt. �� (Bezeichnung des Prüfpräparats) wurde bisher bei ca. ........... Personen geprüft (Erstanwendung muss besonders hervorgehoben werden). Im Rahmen der geplanten klinischen Prüfung wird untersucht, wie gut �� (Bezeichnung des Prüfpräparats) von Ihnen vertragen wird und wie Ihr Körper �� (Bezeichnung des Prüfpräparats) aufnimmt, abbaut und ausscheidet.

Den Studienzweck allgemein verständlich beschreiben; bei mehreren Zielsetzungen

sollten diese in der Rangfolge ihrer Bedeutung für die klinische Prüfung aufgeführt werden.

2. Erhalte ich das Prüfpräparat auf jeden Fall?

Alternativ entweder

Jeder Studienteilnehmer erhält �� (Bezeichnung des Prüfpräparats) einmal (x mal im Abstand von

… Tagen / Wochen) in der Dosierung von … (Dosisgruppe angeben). Die Einnahme erfolgt ........... (entweder als Tablette / Kapsel oder genauen Applikationsweg angeben).

oder

(placebokontrollierte Studie):

Im Rahmen dieser klinischen Prüfung wird �� (Bezeichnung des Prüfpräparats) mit einem Placebo verglichen. Bei einem Placebo handelt es sich um eine identisch aussehende ........... (z. B. Tablette oder Kapsel), die jedoch keinen Wirkstoff enthält. Im Falle Ihrer Teilnahme werden Sie entweder �� (Bezeichnung des Prüfpräparats) oder das Placebo erhalten. Der Vergleich mit dem Placebo dient dazu, die unerwünschten Wirkungen von �� (Bezeichnung des Prüfpräparats) besser beurteilen zu können. Ob Sie das Prüfpräparat oder das Placebo erhalten, entscheidet ein zuvor festgelegtes Zufallsverfahren, vergleichbar mit dem Werfen einer Münze; dieses wird Randomisierung genannt. Die Wahrscheinlichkeit, �� (Bezeichnung des Prüfpräparats) zu erhalten, beträgt ........... %.

oder

(Studie mit Vergleichspräparat)

Im Rahmen dieser klinischen Prüfung wird �� (Bezeichnung des Prüfpräparats) mit ��

(Bezeichnung des Vergleichspräparats) verglichen, einem bereits für die Behandlung von �� (Name der Erkrankung) zugelassenen Arzneimittel. Im Falle Ihrer Teilnahme werden Sie entweder �� oder �� erhalten. Ob sie �� oder �� erhalten, entscheidet der Zufall (dieses Verfahren wird Randomisierung genannt). Die Wahrscheinlichkeit, �� (Bezeichnung des Prüfpräparats) zu erhalten, beträgt ........... %. Zur objektiven Gewinnung von Studiendaten ist es notwendig, dass weder Sie noch Ihr Prüfarzt wissen, welches Präparat Sie einnehmen (dieses Verfahren wird als „doppelblind“ bezeichnet). Sollte es aus Sicherheitsgründen notwendig sein, kann unverzüglich festgestellt werden, welches Präparat Sie erhalten haben (falls andere Art der Verblindung vorgenommen wird, Text anpassen).



3. Wie ist der Ablauf der Studie und was muss ich bei Teilnahme beachten?

Vor Aufnahme in diese klinische Prüfung werden Sie zu Ihren Vorerkrankungen und Ihrem aktuellen Gesundheitsstatus befragt, und Sie werden einer umfassenden ärztlichen Untersuchung unterzogen. Dazu gehört insbesondere ........... (Blutdruckmessung

u. ä.). Die Möglichkeit Ihrer weiteren Teilnahme an dieser klinischen Prüfung wird von den Ergebnissen dieser Voruntersuchung abhängen. Bei Teilnahme an der Studie müssen Sie ........... .

Hier allgemein verständlich und übersichtlich nur studienbedingte Maßnahmen aufführen (ggf. graphische Darstellung), z. B.

� Gesamtdauer der Teilnahme � Einnahme des Prüfpräparats, Eimal-/Mehrfachapplikation, zeitlicher Abstand zwischen den einzelnen

Dosisgruppen � ggf. Absetzen anderer Medikamente (auch rezeptfreie) � Besuche in Prüfstelle, zeitlicher Aufwand pro Visite (stationäre Aufenthalte besonders angeben) � Untersuchungen (z. B. Röntgenuntersuchungen, Blutentnahmen –

Wie oft? Wie viel jeweils? Wie viel insgesamt?) � Hinweise auf Bedeutung der Einhaltung von Besuchsterminen

für die Sicherheit der Probanden und für den Erfolg der klinischen Prüfung � Nachbeobachtungen

Zusätzliche Medikamente (auch rezeptfreie), von denen der Prüfarzt noch nichts weiß, dürfen Sie – außer bei Notfällen – nur nach Rücksprache mit Ihrem Prüfarzt einnehmen. Wenn Sie von anderen Ärzten behandelt werden, müssen Sie diese über Ihre Teilnahme an der klinischen Prüfung informieren. Auch Ihr Prüfarzt muss über jede medizinische Behandlung, die Sie durch einen anderen Arzt während der klinischen Prüfung erhalten, informiert werden. Sie erhalten einen Studienausweis, den Sie auch für den Notfall immer mit sich führen sollten. Alle Prüfpräparate/Medikamente, die Sie im Verlauf dieser klinischen Prüfung bekommen, sollten Sie so sicher aufbewahren, dass sie für Kinder oder andere Personen, die die möglichen Risiken nicht einschätzen können, nicht erreichbar sind. Die Abgabe an Dritte ist untersagt.

Sofern zutreffend, spezielle Anweisungen zur Lagerung der Medikamente z. B. im Kühlschrank.

4. Welchen persönlichen Nutzen habe ich von der Teilnahme an der Studie?

Sie werden durch die Teilnahme an dieser Studie außer einer ärztlichen Untersuchung voraussichtlich keinen persönlichen Gesundheitsnutzen haben. Die Ergebnisse der Studie können aber möglicherweise dazu beitragen, die Behandlung von �� (Name der Erkrankung)

zukünftig zu verbessern/besser beurteilen zu können.

5. Welche Risiken sind mit der Teilnahme an der Studie verbunden?

Hier nur studienbedingte Risiken aufführen!

Dabei sind bekannte und mögliche Risiken, Beschwerden und unerwünschte Wirkungen des Prüfpräparats sowie der Vergleichspräparate zu beschreiben. Darüber hinaus müssen mögliche Risiken im Zusammenhang mit studienbedingten Maßnahmen genannt werden.



Es sollen für den Probanden verständliche Begriffe verwendet werden. Die Häufigkeiten unerwünschter Wirkungen sollen beschrieben werden. Dazu sollen folgende Begriffe mit den entsprechenden Prozentangaben verwendet werden: „sehr häufig“ (> 10 %), „häufig“ (1 – 10 %), „gelegentlich“ (0,1 – 1 %) und „selten“ (< 0,1 %). Ggf. ist auf unterschiedliche Dosisgruppen und damit verbundene Risiken hinzuweisen. Je größer die Gefahren sind, um so deutlicher muss auf sie hingewiesen werden, auch wenn sie selten auftreten.

Die Einnahme/Anwendung von �� (Bezeichnung des Prüfpräparats) kann zu unerwünschten Wirkungen oder Beschwerden führen. Da �� (Bezeichnung des Prüfpräparats) zum ersten Mal am Menschen eingesetzt wird, können Angaben darüber nur aus tierexperimentellen Untersuchungen abgeleitet werden. Bei Versuchen an Tieren traten folgende unerwünschten Wirkungen auf:

Relevante unerwünschte Wirkungen auflisten, insbesondere solche, die an Primaten gefunden wurden; Angabe von Schwellendosen und Sicherheitsabstand;

Hinweis, dass in höheren Dosisstufen eher mit unerwünschten Wirkungen zu rechnen ist.

Da �� (Bezeichnung des Prüfpräparats) zum ersten Mal am Menschen eingesetzt wird, können weitere, bisher nicht bekannte unerwünschte Wirkungen auftreten.

alternativ (Wenn schon Erfahrungen am Menschen vorliegen)

Die Einnahme/Applikation von �� (Bezeichnung des Prüfpräparats) kann zu unerwünschten Wirkungen oder Beschwerden führen. Die bislang beobachteten unerwünschten Wirkungen und Beschwerden umfassen: ........... . Wie bei jeder neuen Substanz können auch bei der Anwendung von �� (Bezeichnung des Prüfpräparats) neue, bisher unbekannte Nebenwirkungen auftreten. Die bislang beobachteten Nebenwirkungen und Beschwerden bei der Behandlung mit ��

(Bezeichnung des Vergleichspräparats) umfassen: ........... . Darüber hinaus können die im Rahmen dieser klinischen Prüfung studienbedingt durchgeführten Maßnahmen mit Risiken behaftet sein oder zu Beschwerden führen. Im Einzelnen handelt es sich um ........... (z. B. Risiken und Belastungen der Blutentnahme, Röntgen). Bitte teilen Sie den Mitarbeitern der Prüfstelle alle Beschwerden, Erkrankungen oder Verletzungen mit, die im Verlauf der klinischen Prüfung auftreten. Falls diese schwerwiegend sind, teilen Sie den Mitarbeitern der Prüfstelle diese bitte umgehend mit, ggf. telefonisch.

Sofern zutreffend, Hinweis auf Gefahren durch Teilnahme am Straßenverkehr, Führen von Maschinen etc

6. Wer darf an dieser klinischen Prüfung nicht teilnehmen?

Sie können an dieser klinischen Prüfung nur teilnehmen, wenn Sie gesund sind und sich nicht gleichzeitig für andere klinische Prüfungen oder andere klinische Forschungsprojekte zur Verfügung stellen oder bis vor kurzem teilgenommen haben (ggf. genaue Karenzzeit angeben).

Die jeweiligen Ausschlusskriterien des Prüfplans sollten nicht in der Probandeninformation aufgeführt werden; vielmehr hat der Prüfarzt die entsprechenden Kriterien zu prüfen.

Für klinische Prüfungen, an denen möglicherweise Frauen im gebärfähigen Alter teilnehmen,

sind die folgenden Absätze einzufügen und ggf. an das Studienprotokoll anzupassen:

Schwangere Frauen dürfen an dieser klinischen Prüfung nicht teilnehmen.



Zu Beginn der klinischen Prüfung müssen sich deshalb alle Frauen einem Schwangerschaftstest unterziehen. Davon ausgenommen sind Frauen nach den Wechseljahren oder solche, die operativ sterilisiert wurden. Durch einen Schwangerschaftstest kann jedoch eine Schwangerschaft erst einige Tage nach der Empfängnis verlässlich nachgewiesen werden. Im Falle Ihrer Teilnahme an dieser klinischen Prüfung müssen Sie zuverlässige Maßnahmen zur Schwangerschaftsverhütung anwenden. Diese sind ........... (die im Prüfplan geforderten

Empfängnisverhütungsmaßnahmen präzise angeben; ggf. Schutzmaßnahmen auch über längere Zeit nach

Ausscheiden aus der Studie). Der Grund dafür ist, dass ........... Alternativen

entweder:

bislang nicht geklärt ist, ob �� (Bezeichnung des Prüfpräparats) zu einer Schädigung des Ungeborenen führen kann/können, wenn es/sie während der Schwangerschaft eingenommen wird/werden.

oder:

aus Tierversuchen/aus der Anwendung am Menschen Hinweise/Belege für ein erhöhtes Risiko einer Schädigung des ungeborenen Lebens vorliegen.

oder:

aus Tierversuchen/aus der Anwendung am Menschen Hinweise/Belege für eine Schädigung des ungeborenen Lebens vorliegen. Sollten Sie während der klinischen Prüfung schwanger werden oder den Verdacht haben, dass Sie schwanger geworden sind, müssen Sie umgehend den Prüfarzt informieren. Auch stillende Frauen dürfen an dieser klinischen Prüfung nicht teilnehmen, da �� (Bezeichnung des Prüfpräparats) mit der Muttermilch in den Körper des Kindes gelangen und zu seiner Schädigung führen könnte(n).

Für Männer notwendige Informationen in Abhängigkeit vom Prüfpräparat hier anfügen.

7. Entstehen für mich Kosten durch die Teilnahme an der klinischen Prüfung? Erhalte ich eine Aufwandsentschädigung?

Durch Ihre Teilnahme an dieser klinischen Prüfung entstehen für Sie keine Kosten (sofern für den Studienteilnehmer im Zusammenhang mit seiner Teilnahme an der klinischen Prüfung Kosten entstehen,

müssen diese spezifiziert werden).

Sofern Probanden für ihre Teilnahme eine Aufwandsentschädigung erhalten, sollte der folgende Absatz angefügt werden:

Für Ihre Teilnahme an dieser klinischen Prüfung erhalten Sie eine Aufwandsentschädigung entsprechend den folgenden Bedingungen: ........... (es sollte genau beschrieben werden, unter welchen Voraussetzungen der Proband wie viel erhält).



8. Bin ich während der klinischen Prüfung versichert?

Bei der klinischen Prüfung eines Arzneimittels sind alle Studienteilnehmer gemäß dem Arzneimittelgesetz versichert. Der Umfang des Versicherungsschutzes ergibt sich aus den Versicherungsunterlagen, die Sie je nach Alternative unten ggf. ergänzen: auf Wunsch ausgehändigt bekommen.

Wenn Sie vermuten, dass durch die Teilnahme an der klinischen Prüfung Ihre Gesundheit geschädigt oder bestehende Leiden verstärkt wurden, müssen Sie dies unverzüglich dem Versicherer

Name und Anschrift der Versicherung: ........... Telefon: ........... Fax: ...........

Versicherungsnummer: ........... direkt anzeigen, gegebenenfalls mit Unterstützung durch Ihren Prüfarzt, um Ihren Versicherungsschutz nicht zu gefährden. Sofern Ihr Prüfarzt Sie dabei unterstützt, erhalten Sie eine Kopie der Meldung. Sofern Sie Ihre Anzeige direkt an den Versicherer richten, informieren Sie bitte zusätzlich Ihren Prüfarzt.

Bei der Aufklärung der Ursache oder des Umfangs eines Schadens müssen Sie mitwirken und alles unternehmen, um den Schaden abzuwenden und zu mindern. Während der Dauer der klinischen Prüfung dürfen Sie sich einer anderen medizinischen Behandlung – außer in Notfällen – nur nach vorheriger Rücksprache mit dem Prüfarzt unterziehen. Von einer erfolgten Notfallbehandlung müssen Sie den Prüfarzt unverzüglich unterrichten.

Alternativ entweder:

Sie erhalten ein Exemplar der Versicherungsbestätigung einschließlich der Versicherungsbedingungen. Wir weisen Sie insbesondere auf § 3 (zu den Ausschlüssen), § 6 (zum Umfang der Leistungen) und § 14 II (zu Ihren Obliegenheiten) hin. (Ggf. an den konkreten Versicherungsvertrag anpassen. Ab 1.1.2008 werden sukzessiv neue Versicherungsbedingungen verwendet. Dann muss der Text lauten: „Wir weisen Sie insbesondere auf Punkt 1.4 (zu den Ausschlüssen), Punkt 3.1 (zum Umfang der Leistungen) und Punkt 4.3 sowie Punkt 4.4. (zu Ihren Obliegenheiten) hin.“)

oder:

Auf Wunsch erhalten Sie ein Exemplar der Versicherungsbedingungen. Wir weisen Sie ferner darauf hin, dass Sie auf dem Weg von und zur Prüfstelle nicht unfallversichert sind/in folgender Weise versichert sind (sofern zutreffend, hier die Angaben zur Versicherung wie oben).

9. Werden mir neue Erkenntnisse während der klinischen Prüfung mitgeteilt?

Sie werden über neue Erkenntnisse, die in Bezug auf diese klinische Prüfung bekannt werden und die für Ihre Bereitschaft zur weiteren Teilnahme wesentlich sein können, informiert. Auf dieser Basis können Sie dann Ihre Entscheidung zur weiteren Teilnahme an dieser klinischen Prüfung überdenken.



10. Kann meine Teilnahme an der klinischen Prüfung vorzeitig beendet werden?

Sie können jederzeit, auch ohne Angabe von Gründen, Ihre Teilnahme beenden, ohne dass Ihnen dadurch irgendwelche Nachteile entstehen. Unter gewissen Umständen ist es aber auch möglich, dass der Prüfarzt oder der Sponsor entscheidet, Ihre Teilnahme an der klinischen Prüfung vorzeitig zu beenden, ohne dass Sie auf die Entscheidung Einfluss haben. Die Gründe hierfür können z. B. sein: � Ihre weitere Teilnahme an der klinischen Prüfung ist ärztlich nicht mehr vertretbar; � es wird die gesamte klinische Prüfung abgebrochen. Sofern Sie sich dazu entschließen, vorzeitig aus der klinischen Prüfung auszuscheiden, oder Ihre Teilnahme aus einem anderen der genannten Gründe vorzeitig beendet wird, ist es für Ihre eigene Sicherheit wichtig, dass Sie sich einer empfohlenen abschließenden Kontrolluntersuchung unterziehen (evtl. sonstige studienspezifische Angaben ergänzen, insbesondere zu etwaigen weiteren Maßnahmen zur Sicherheit der Studienteilnehmer).

Der Prüfarzt wird mit Ihnen besprechen, ob und wann weitere Kontrolluntersuchungen notwendig sind.

11. Was geschieht mit meinen Daten?

Während der klinischen Prüfung werden medizinische Befunde und persönliche Informationen von Ihnen erhoben und in der Prüfstelle in Ihrer persönlichen Akte niedergeschrieben oder elektronisch gespeichert. Die für die klinische Prüfung wichtigen Daten werden zusätzlich in pseudonymisierter Form gespeichert, ausgewertet und gegebenenfalls weitergegeben. Pseudonymisiert bedeutet, dass keine Angaben von Namen oder Initialen verwendet werden, sondern nur ein Nummern- und/oder Buchstabencode, evtl. mit Angabe des Geburtsjahres. Die Daten sind gegen unbefugten Zugriff gesichert. Eine Entschlüsselung erfolgt nur unter den vom Gesetz vorgeschriebenen Voraussetzungen oder in folgenden Fällen ........... (Angaben aus dem Studienprotokoll). Das Arzneimittelgesetz enthält nähere Vorgaben für den erforderlichen Umfang der Einwilligung in die Datenerhebung und -verwendung. Einzelheiten, insbesondere zur Möglichkeit eines Widerrufs, entnehmen Sie bitte der Einwilligungserklärung, die im Anschluss an diese Probandeninformation abgedruckt ist.

12. Was geschieht mit meinen Blutproben/Gewebeproben/Aufnahmen mit bildgebenden Verfahren (an die jeweilige Studie anpassen)?


Die Blutproben/Gewebeproben/Aufnahmen mit bildgebenden Verfahren werden ausschließlich für diese klinische Prüfung verwendet. Etwaiges Restmaterial wird bei Abschluss der Prüfung vernichtet.



oder:

Die Blutproben/Gewebeproben/Aufnahmen mit bildgebenden Verfahren werden nach Abschluss der Prüfung in folgender Weise verwendet / aufbewahrt: ........... . Erläuterung über Anonymisierung/Pseudonymisierung, soweit voraussehbar Verwendung für andere Zwecke, soweit voraussehbar Dauer und Ort der Aufbewahrung etc., ggf. Verweis auf weiteres Informationsmaterial.

13. An wen wende ich mich bei weiteren Fragen?

Beratungsgespräche an der Prüfstelle

Sie haben stets die Gelegenheit zu weiteren Beratungsgesprächen mit dem auf Seite 1 genannten oder einem anderen Prüfarzt. Kontaktstelle

Es existiert außerdem eine Kontaktstelle bei der zuständigen Bundesoberbehörde. Teilnehmer an klinischen Prüfungen, ihre gesetzlichen Vertreter oder Bevollmächtigten können sich an diese Kontaktstelle wenden:

Alternativ

- nur die zuständige Stelle angeben - entweder:

Bundesinstitut für Arzneimittel und Medizinprodukte Fachgebiet Klinische Prüfung / Inspektionen

Kurt-Georg-Kiesinger-Allee 3

53175 Bonn

Telefon: 0228 / 207-4318 Fax: 0228 / 207-4355 e-mail: [email protected]

oder:

Paul-Ehrlich-Institut Referat Klinische Prüfungen

Paul-Ehrlich-Str. 51-59

63225 Langen




Prüfstelle: ........... Prüfarzt: ........... EUDRACT-Nr. ...........


Einwilligungserklärung

............................................................................................................................ Name des Probanden in Druckbuchstaben

geb. am ........................................ Teilnehmer-Nr. ........................................ Ich bin in einem persönlichen Gespräch durch den Prüfarzt ............................................................................................................................ Name der Ärztin/des Arztes

ausführlich und verständlich über das Prüfmedikament (und ggf. das Vergleichsmedikament) sowie über Wesen, Bedeutung, Risiken und Tragweite der klinischen Prüfung aufgeklärt worden. Ich habe darüber hinaus den Text der Probandeninformation sowie die hier nachfolgend abgedruckte Datenschutzerklärung gelesen und verstanden. Ich hatte die Gelegenheit, mit dem Prüfarzt über die Durchführung der klinischen Prüfung zu sprechen. Alle meine Fragen wurden zufrieden stellend beantwortet. Möglichkeit zur Dokumentation zusätzlicher Fragen seitens des Probanden oder sonstiger Aspekte des Aufklärungsgesprächs:

Ich hatte ausreichend Zeit, mich zu entscheiden. Mir ist bekannt, dass ich jederzeit und ohne Angabe von Gründen meine Einwilligung zur Teilnahme an der Prüfung zurückziehen kann (mündlich oder schriftlich), ohne dass mir daraus Nachteile entstehen.



Datenschutz:

Mir ist bekannt, dass bei dieser klinischen Prüfung personenbezogene Daten, insbesondere medizinische Befunde über mich erhoben, gespeichert und ausgewertet werden sollen. Die Verwendung der Angaben über meine Gesundheit erfolgt nach gesetzlichen Bestimmungen und setzt vor der Teilnahme an der klinischen Prüfung folgende freiwillig abgegebene Einwilligungserklärung voraus, das heißt ohne die nachfolgende Einwilligung kann ich nicht an der klinischen Prüfung teilnehmen. 1. Ich erkläre mich damit einverstanden, dass im Rahmen dieser klinischen Prüfung

personenbezogene Daten, insbesondere Angaben über meine Gesundheit, über mich erhoben und in Papierform sowie auf elektronischen Datenträgern bei/in ........... (Institution/Ort der Aufzeichnung angeben) aufgezeichnet werden. Soweit erforderlich, dürfen die erhobenen Daten pseudonymisiert (verschlüsselt) weitergegeben werden:

a) an ........... , den Sponsor oder eine von diesem beauftragte Stelle zum Zwecke der wissenschaftlichen Auswertung,

b) im Falle eines Antrags auf Zulassung: an den Antragsteller und die für die Zulassung zuständige Behörde ........... (z. B. Bundesinstitut für Arzneimittel und Medizinprodukte),

c) im Falle unerwünschter Ereignisse: an ..........., den Sponsor, an die jeweils zuständige Ethik-Kommission und die zuständige Bundesoberbehörde ........... (hier die Bundesoberbehörde eintragen, z. B. Bundesinstitut für Arzneimittel und Medizinprodukte), sowie von dieser an die Europäische Datenbank.

2. Außerdem erkläre ich mich damit einverstanden, dass autorisierte und zur Verschwiegenheit

verpflichtete Beauftragte des Sponsors sowie die zuständigen Überwachungsbehörden in meine beim Prüfarzt vorhandenen personenbezogenen Daten, insbesondere meine Gesundheitsdaten, Einsicht nehmen, soweit dies für die Überprüfung der ordnungsgemäßen Durchführung der Studie notwendig ist. Für diese Maßnahme entbinde ich den Prüfarzt von der ärztlichen Schweigepflicht.

3. Die Einwilligung zur Erhebung und Verarbeitung meiner personenbezogenen Daten, insbesondere

der Angaben über meine Gesundheit, ist unwiderruflich. Ich bin bereits darüber aufgeklärt worden, dass ich jederzeit die Teilnahme an der klinischen Prüfung beenden kann. Im Fall eines solchen Widerrufs meiner Einwilligung, an der Studie teilzunehmen, erkläre ich mich damit einverstanden, dass die bis zu diesem Zeitpunkt gespeicherten Daten weiterhin verwendet werden dürfen, soweit dies erforderlich ist, um

a) Wirkungen des zu prüfenden Arzneimittels festzustellen,

b) sicherzustellen, dass meine schutzwürdigen Interessen nicht beeinträchtigt werden,

c) der Pflicht zur Vorlage vollständiger Zulassungsunterlagen zu genügen. 4. Ich erkläre mich damit einverstanden, dass meine Daten nach Beendigung oder Abbruch der

Prüfung mindestens zehn Jahre aufbewahrt werden, wie es die Vorschriften über die klinische Prüfung von Arzneimitteln bestimmen. Danach werden meine personenbezogenen Daten gelöscht, soweit nicht gesetzliche, satzungsmäßige oder vertragliche Aufbewahrungsfristen entgegenstehen (vertraglich vereinbarte Fristen müssen hier genannt werden).

5. Ich bin über folgende gesetzliche Regelung informiert: Falls ich meine Einwilligung, an der Studie

teilzunehmen, widerrufe, müssen alle Stellen, die meine personenbezogenen Daten, insbesondere Gesundheitsdaten, gespeichert haben, unverzüglich prüfen, inwieweit die gespeicherten Daten für die in Nr. 3 a) bis c) genannten Zwecke noch erforderlich sind.

Nicht mehr benötigte Daten sind unverzüglich zu löschen. 6. Ich bin damit einverstanden, dass mein Hausarzt ................................................................................................................................... Name

über meine Teilnahme an der klinischen Prüfung informiert wird (falls nicht gewünscht, bitte streichen).



Ich erkläre mich bereit,

an der oben genannten klinischen Prüfung

freiwillig teilzunehmen. Ein Exemplar der Probanden-Information und -Einwilligung (sofern zutreffend: sowie die

Versicherungsbedingungen) habe ich erhalten. Ein Exemplar verbleibt im Prüfzentrum. ........................................................................................................................... Name des Probanden in Druckbuchstaben

.................................... ............................................................................... Datum Unterschrift des Probanden

Ich habe das Aufklärungsgespräch geführt und die Einwilligung des Probanden eingeholt. ........................................................................................................................... Name des Prüfarztes/der Prüfärztin in Druckbuchstaben

.................................... ............................................................................... Datum Unterschrift des aufklärenden Prüfarztes/der Prüfärztin

Annex 7b Best Practice Guide for Regulatory Affairs in a German CRO


MUSTERTEXT

für die Probanden-Information und -Einwilligung zur Durchführung einer klinischen Prüfung eines Arzneimittels

mit volljährigen einwilligungsfähigen Probanden1

Hinweis Dieser Mustertext basiert auf dem Mustertext des Arbeitskreises

Medizinischer Ethik-Kommissionen (Stand 14.06.2008) enthält jedoch 4 Abweichungen

Alle kursiv gedruckten Textstellen enthalten Hinweise zum Erstellen

der Probanden-Information und -Einwilligung

Prüfstelle: ........... Angaben zur jeweiligen Prüfstelle mit Adresse und Telefonnummer Prüfarzt: ........... EUDRACT-Nr. ........... Diese gehört wie die Angabe der Version der Probanden-Information

auch in die fortlaufende Fußzeile


Sehr geehrte Dame, sehr geehrter Herr, wir möchten Sie fragen, ob Sie bereit sind, an der von uns vorgesehenen klinischen Prüfung (Studie) teilzunehmen. Klinische Prüfungen sind notwendig, um Erkenntnisse über die Wirksamkeit und Verträglichkeit von Arzneimitteln zu gewinnen oder zu erweitern. Deshalb schreibt der Gesetzgeber im Arzneimittelgesetz vor, dass neue Arzneimittel klinisch geprüft werden müssen. Die klinische Prüfung, die wir Ihnen hier vorstellen, wurde – wie es das Gesetz verlangt – von der zuständigen Ethikkommission zustimmend bewertet und von der zuständigen Behörde genehmigt. Diese klinische Prüfung wird in........... (Ort der

Durchführung)/an mehreren Orten durchgeführt; es sollen insgesamt ungefähr ........... Personen daran teilnehmen. Die Studie wird veranlasst, organisiert und finanziert durch ........... (Name, Sitz), den Sponsor dieser Studie. Ihre Teilnahme an dieser klinischen Prüfung ist freiwillig. Sie werden in diese Prüfung also nur dann einbezogen, wenn Sie dazu schriftlich Ihre Einwilligung erklären. Sofern Sie nicht an der klinischen Prüfung teilnehmen oder später aus ihr ausscheiden möchten, erwachsen Ihnen daraus keine Nachteile. Der Prüfarzt hat Ihnen bereits eine Reihe von Informationen zu der geplanten Studie gegeben. Der nachfolgende Text soll Ihnen die Ziele und den Ablauf erläutern. Anschließend wird ein Prüfarzt das Aufklärungsgespräch mit Ihnen führen. Bitte zögern Sie nicht, alle Punkte anzusprechen, die Ihnen unklar sind. Sie werden danach ausreichend Bedenkzeit erhalten, um über Ihre Teilnahme zu entscheiden.

1

Im Rahmen dieses Textes schließt die männliche Bezeichnung stets die weibliche Bezeichnung mit ein.



1. Warum wird diese Prüfung durchgeführt?

�� (Bezeichnung des Prüfpräparats) ist ein Arzneimittel in klinischer Erprobung und wird zur Behandlung von �� (Name der Erkrankung) entwickelt, d. h. es ist von der Behörde für die Behandlung dieser Krankheit noch nicht zugelassen (ggf. Hinweis auf bereits bestehende

Zulassungen für andere Indikationen). In der geplanten klinischen Prüfung wird �� (Bezeichnung des Prüfpräparats) zum ersten Mal (zum ersten Mal in der hier vorgesehenen Dosierung von …/zum ersten

Mal in der hier vorgesehenen Dauer von … Tagen/Wochen) am Menschen eingesetzt. �� (Bezeichnung des Prüfpräparats) wurde bisher bei ca. ........... Personen geprüft (Erstanwendung muss besonders hervorgehoben werden). Im Rahmen der geplanten klinischen Prüfung wird untersucht, wie gut �� (Bezeichnung des Prüfpräparats) von Ihnen vertragen wird und wie Ihr Körper �� (Bezeichnung des Prüfpräparats) aufnimmt, abbaut und ausscheidet.

Den Studienzweck allgemein verständlich beschreiben; bei mehreren Zielsetzungen

sollten diese in der Rangfolge ihrer Bedeutung für die klinische Prüfung aufgeführt werden.

2. Erhalte ich das Prüfpräparat auf jeden Fall?

Alternativ entweder

Jeder Studienteilnehmer erhält �� (Bezeichnung des Prüfpräparats) einmal (x mal im Abstand von

… Tagen / Wochen) in der Dosierung von … (Dosisgruppe angeben). Die Einnahme erfolgt ........... (entweder als Tablette / Kapsel oder genauen Applikationsweg angeben).

oder (placebokontrollierte Studie):

Im Rahmen dieser klinischen Prüfung wird �� (Bezeichnung des Prüfpräparats) mit einem Placebo verglichen. Bei einem Placebo handelt es sich um eine identisch aussehende ........... (z. B. Tablette oder Kapsel), die jedoch keinen Wirkstoff enthält. Im Falle Ihrer Teilnahme werden Sie entweder �� (Bezeichnung des Prüfpräparats) oder das Placebo erhalten. Der Vergleich mit dem Placebo dient dazu, die unerwünschten Wirkungen von �� (Bezeichnung des Prüfpräparats) besser beurteilen zu können. Ob Sie das Prüfpräparat oder das Placebo erhalten, entscheidet ein zuvor festgelegtes Zufallsverfahren, vergleichbar mit dem Werfen einer Münze; dieses wird Randomisierung genannt. Die Wahrscheinlichkeit, �� (Bezeichnung des Prüfpräparats) zu erhalten, beträgt ........... %.

oder

(Studie mit Vergleichspräparat)

Im Rahmen dieser klinischen Prüfung wird �� (Bezeichnung des Prüfpräparats) mit ��

(Bezeichnung des Vergleichspräparats) verglichen, einem bereits für die Behandlung von �� (Name der Erkrankung) zugelassenen Arzneimittel. Im Falle Ihrer Teilnahme werden Sie entweder �� oder �� erhalten. Ob sie �� oder �� erhalten, entscheidet der Zufall (dieses Verfahren wird Randomisierung genannt). Die Wahrscheinlichkeit, �� (Bezeichnung des Prüfpräparats) zu erhalten, beträgt ........... %. Zur objektiven Gewinnung von Studiendaten ist es notwendig, dass weder Sie noch Ihr Prüfarzt wissen, welches Präparat Sie einnehmen (dieses Verfahren wird als „doppelblind“ bezeichnet). Sollte es aus Sicherheitsgründen notwendig sein, kann unverzüglich festgestellt werden, welches Präparat Sie erhalten haben (falls andere Art der Verblindung vorgenommen wird, Text anpassen).



3. Wie ist der Ablauf der Studie und was muss ich bei Teilnahme beachten?

Vor Aufnahme in diese klinische Prüfung werden Sie zu Ihren Vorerkrankungen und Ihrem aktuellen Gesundheitsstatus befragt, und Sie werden einer umfassenden ärztlichen Untersuchung unterzogen. Dazu gehört insbesondere ........... (Blutdruckmessung

u. ä.). Die Möglichkeit Ihrer weiteren Teilnahme an dieser klinischen Prüfung wird von den Ergebnissen dieser Voruntersuchung abhängen. Bei Teilnahme an der Studie müssen Sie ........... .

Hier allgemein verständlich und übersichtlich nur studienbedingte Maßnahmen aufführen (ggf. graphische Darstellung), z. B.

� Gesamtdauer der Teilnahme � Einnahme des Prüfpräparats, Eimal-/Mehrfachapplikation, zeitlicher Abstand zwischen den einzelnen

Dosisgruppen � ggf. Absetzen anderer Medikamente (auch rezeptfreie) � Besuche in Prüfstelle, zeitlicher Aufwand pro Visite (stationäre Aufenthalte besonders angeben) � Untersuchungen (z. B. Röntgenuntersuchungen, Blutentnahmen –

Wie oft? Wie viel jeweils? Wie viel insgesamt?) � Hinweise auf Bedeutung der Einhaltung von Besuchsterminen

für die Sicherheit der Probanden und für den Erfolg der klinischen Prüfung � Nachbeobachtungen

Zusätzliche Medikamente (auch rezeptfreie), von denen der Prüfarzt noch nichts weiß, dürfen Sie – außer bei Notfällen – nur nach Rücksprache mit Ihrem Prüfarzt einnehmen. Wenn Sie von anderen Ärzten behandelt werden, müssen Sie diese über Ihre Teilnahme an der klinischen Prüfung informieren. Auch Ihr Prüfarzt muss über jede medizinische Behandlung, die Sie durch einen anderen Arzt während der klinischen Prüfung erhalten, informiert werden. Sie erhalten einen Studienausweis, den Sie auch für den Notfall immer mit sich führen sollten. Alle Prüfpräparate/Medikamente, die Sie im Verlauf dieser klinischen Prüfung bekommen, sollten Sie so sicher aufbewahren, dass sie für Kinder oder andere Personen, die die möglichen Risiken nicht einschätzen können, nicht erreichbar sind. Die Abgabe an Dritte ist untersagt.

Sofern zutreffend, spezielle Anweisungen zur Lagerung der Medikamente z. B. im Kühlschrank.

4. Welchen persönlichen Nutzen habe ich von der Teilnahme an der Studie?

Sie werden durch die Teilnahme an dieser Studie außer einer ärztlichen Untersuchung voraussichtlich keinen persönlichen Gesundheitsnutzen haben. Die Ergebnisse der Studie können aber möglicherweise dazu beitragen, die Behandlung von �� (Name der Erkrankung)

zukünftig zu verbessern/besser beurteilen zu können.

5. Welche Risiken sind mit der Teilnahme an der Studie verbunden?

Hier nur studienbedingte Risiken aufführen!

Dabei sind bekannte und mögliche Risiken, Beschwerden und unerwünschte Wirkungen des Prüfpräparats sowie der Vergleichspräparate zu beschreiben. Darüber hinaus müssen mögliche Risiken im Zusammenhang mit studienbedingten Maßnahmen genannt werden.



Es sollen für den Probanden verständliche Begriffe verwendet werden. Die Häufigkeiten unerwünschter Wirkungen sollen beschrieben werden. Dazu sollen folgende Begriffe mit den entsprechenden Prozentangaben verwendet werden: „sehr häufig“ (> 10 %), „häufig“ (1 – 10 %), „gelegentlich“ (0,1 – 1 %) und „selten“ (< 0,1 %). Ggf. ist auf unterschiedliche Dosisgruppen und damit verbundene Risiken hinzuweisen. Je größer die Gefahren sind, um so deutlicher muss auf sie hingewiesen werden, auch wenn sie selten auftreten.

Die Einnahme/Anwendung von �� (Bezeichnung des Prüfpräparats) kann zu unerwünschten Wirkungen oder Beschwerden führen. Da �� (Bezeichnung des Prüfpräparats) zum ersten Mal am Menschen eingesetzt wird, können Angaben darüber nur aus tierexperimentellen Untersuchungen abgeleitet werden. Bei Versuchen an Tieren traten folgende unerwünschten Wirkungen auf:

Relevante unerwünschte Wirkungen auflisten, insbesondere solche, die an Primaten gefunden wurden; Angabe von Schwellendosen und Sicherheitsabstand;

Hinweis, dass in höheren Dosisstufen eher mit unerwünschten Wirkungen zu rechnen ist.

Da �� (Bezeichnung des Prüfpräparats) zum ersten Mal am Menschen eingesetzt wird, können weitere, bisher nicht bekannte unerwünschte Wirkungen auftreten.

alternativ (Wenn schon Erfahrungen am Menschen vorliegen)

Die Einnahme/Applikation von �� (Bezeichnung des Prüfpräparats) kann zu unerwünschten Wirkungen oder Beschwerden führen. Die bislang beobachteten unerwünschten Wirkungen und Beschwerden umfassen: ........... . Wie bei jeder neuen Substanz können auch bei der Anwendung von �� (Bezeichnung des Prüfpräparats) neue, bisher unbekannte Nebenwirkungen auftreten. Die bislang beobachteten Nebenwirkungen und Beschwerden bei der Behandlung mit ��

(Bezeichnung des Vergleichspräparats) umfassen: ........... . Darüber hinaus können die im Rahmen dieser klinischen Prüfung studienbedingt durchgeführten Maßnahmen mit Risiken behaftet sein oder zu Beschwerden führen. Im Einzelnen handelt es sich um ........... (z. B. Risiken und Belastungen der Blutentnahme, Röntgen). Bitte teilen Sie den Mitarbeitern der Prüfstelle alle Beschwerden, Erkrankungen oder Verletzungen mit, die im Verlauf der klinischen Prüfung auftreten. Falls diese schwerwiegend sind, teilen Sie den Mitarbeitern der Prüfstelle diese bitte umgehend mit, ggf. telefonisch.

Sofern zutreffend, Hinweis auf Gefahren durch Teilnahme am Straßenverkehr, Führen von Maschinen etc

6. Wer darf an dieser klinischen Prüfung nicht teilnehmen?

Sie können an dieser klinischen Prüfung nur teilnehmen, wenn Sie gesund sind und sich nicht gleichzeitig für andere klinische Prüfungen oder andere klinische Forschungsprojekte zur Verfügung stellen oder bis vor kurzem teilgenommen haben (ggf. genaue Karenzzeit angeben).

Die jeweiligen Ausschlusskriterien des Prüfplans sollten nicht in der Probandeninformation aufgeführt werden; vielmehr hat der Prüfarzt die entsprechenden Kriterien zu prüfen.

Für klinische Prüfungen, an denen möglicherweise Frauen im gebärfähigen Alter teilnehmen,

sind die folgenden Absätze einzufügen und ggf. an das Studienprotokoll anzupassen:



Schwangere Frauen dürfen an dieser klinischen Prüfung nicht teilnehmen. Zu Beginn der klinischen Prüfung müssen sich deshalb alle Frauen einem Schwangerschaftstest unterziehen. Davon ausgenommen sind Frauen nach den Wechseljahren oder solche, die operativ sterilisiert wurden. Durch einen Schwangerschaftstest kann jedoch eine Schwangerschaft erst einige Tage nach der Empfängnis verlässlich nachgewiesen werden. Im Falle Ihrer Teilnahme an dieser klinischen Prüfung müssen Sie zuverlässige Maßnahmen zur Schwangerschaftsverhütung anwenden. Diese sind ........... (die im Prüfplan geforderten

Empfängnisverhütungsmaßnahmen präzise angeben; ggf. Schutzmaßnahmen auch über längere Zeit nach

Ausscheiden aus der Studie). Der Grund dafür ist, dass ........... Alternativen

entweder:

bislang nicht geklärt ist, ob �� (Bezeichnung des Prüfpräparats) zu einer Schädigung des Ungeborenen führen kann/können, wenn es/sie während der Schwangerschaft eingenommen wird/werden.

oder:

aus Tierversuchen/aus der Anwendung am Menschen Hinweise/Belege für ein erhöhtes Risiko einer Schädigung des ungeborenen Lebens vorliegen.

oder:

aus Tierversuchen/aus der Anwendung am Menschen Hinweise/Belege für eine Schädigung des ungeborenen Lebens vorliegen. Sollten Sie während der klinischen Prüfung schwanger werden oder den Verdacht haben, dass Sie schwanger geworden sind, müssen Sie umgehend den Prüfarzt informieren. Auch stillende Frauen dürfen an dieser klinischen Prüfung nicht teilnehmen, da �� (Bezeichnung des Prüfpräparats) mit der Muttermilch in den Körper des Kindes gelangen und zu seiner Schädigung führen könnte(n).

Für Männer notwendige Informationen in Abhängigkeit vom Prüfpräparat hier anfügen.

7. Entstehen für mich Kosten durch die Teilnahme an der klinischen Prüfung? Erhalte ich eine Aufwandsentschädigung?

Durch Ihre Teilnahme an dieser klinischen Prüfung entstehen für Sie keine Kosten (sofern für den Studienteilnehmer im Zusammenhang mit seiner Teilnahme an der klinischen Prüfung Kosten entstehen,

müssen diese spezifiziert werden).

Sofern Probanden für ihre Teilnahme eine Aufwandsentschädigung erhalten, sollte der folgende Absatz angefügt werden:

Für Ihre Teilnahme an dieser klinischen Prüfung erhalten Sie eine Aufwandsentschädigung entsprechend den folgenden Bedingungen: ........... (es sollte genau beschrieben werden, unter welchen Voraussetzungen der Proband wie viel erhält).



8. Bin ich während der klinischen Prüfung versichert?

Bei der klinischen Prüfung eines Arzneimittels sind alle Studienteilnehmer gemäß dem Arzneimittelgesetz versichert. Der Umfang des Versicherungsschutzes ergibt sich aus den Versicherungsunterlagen, die Sie je nach Alternative unten ggf. ergänzen: auf Wunsch ausgehändigt bekommen.

Wenn Sie vermuten, dass durch die Teilnahme an der klinischen Prüfung Ihre Gesundheit geschädigt oder bestehende Leiden verstärkt wurden, müssen Sie dies unverzüglich dem Versicherer

Name und Anschrift der Versicherung: ........... Telefon: ........... Fax: ...........

Versicherungsnummer: ........... direkt anzeigen, gegebenenfalls mit Unterstützung durch Ihren Prüfarzt, um Ihren Versicherungsschutz nicht zu gefährden. Sofern Ihr Prüfarzt Sie dabei unterstützt, erhalten Sie eine Kopie der Meldung. Sofern Sie Ihre Anzeige direkt an den Versicherer richten, informieren Sie bitte zusätzlich Ihren Prüfarzt.

Bei der Aufklärung der Ursache oder des Umfangs eines Schadens müssen Sie mitwirken und alles unternehmen, um den Schaden abzuwenden und zu mindern. Während der Dauer der klinischen Prüfung dürfen Sie sich einer anderen medizinischen Behandlung – außer in Notfällen – nur nach vorheriger Rücksprache mit dem Prüfarzt unterziehen. Von einer erfolgten Notfallbehandlung müssen Sie den Prüfarzt unverzüglich unterrichten.


Sie erhalten ein Exemplar der vollständigen Versicherungsunterlagen (Versicherungsbestätigung einschließlich der Versicherungsbedingungen). Wir weisen Sie insbesondere auf § 3 (zu den Ausschlüssen), § 6 (zum Umfang der Leistungen) und § 14 II (zu Ihren Obliegenheiten) hin. (Ggf. an den konkreten Versicherungsvertrag anpassen. Ab 1.1.2008 werden sukzessiv neue Versicherungsbedingungen verwendet. Dann muss der Text lauten: „Wir weisen Sie insbesondere auf Punkt 1.4 (zu den Ausschlüssen), Punkt 3.1 (zum Umfang der Leistungen) und Punkt 4.3 sowie Punkt 4.4. (zu Ihren Obliegenheiten) hin.“)

oder:

Auf Wunsch erhalten Sie ein Exemplar der Versicherungsbedingungen. Wir weisen Sie ferner darauf hin, dass Sie auf dem Weg von und zur Prüfstelle nicht unfallversichert sind/in folgender Weise versichert sind (Angabe der

Wegeunfallversicherung).

9. Werden mir neue Erkenntnisse während der klinischen Prüfung mitgeteilt?

Sie werden über neue Erkenntnisse, die in Bezug auf diese klinische Prüfung bekannt werden und die für Ihre Bereitschaft zur weiteren Teilnahme wesentlich sein können, informiert. Auf dieser Basis können Sie dann Ihre Entscheidung zur weiteren Teilnahme an dieser klinischen Prüfung überdenken.



10. Kann meine Teilnahme an der klinischen Prüfung vorzeitig beendet werden?

Sie können jederzeit, auch ohne Angabe von Gründen, Ihre Teilnahme beenden, ohne dass Ihnen dadurch irgendwelche Nachteile entstehen. Unter gewissen Umständen ist es aber auch möglich, dass der Prüfarzt oder der Sponsor entscheidet, Ihre Teilnahme an der klinischen Prüfung vorzeitig zu beenden, ohne dass Sie auf die Entscheidung Einfluss haben. Die Gründe hierfür können z. B. sein: � Ihre weitere Teilnahme an der klinischen Prüfung ist ärztlich nicht mehr vertretbar; � es wird die gesamte klinische Prüfung abgebrochen. � Ihre weitere Teilnahme an der klinischen Prüfung ist aufgrund Ihrer Missachtung der Studienanordnungen (z.B. Punkt 3, Einnahme zusätzlicher Medikamente ohne Rücksprache mit dem Prüfarzt) nicht mehr vertretbar

� es wird die gesamte klinische Prüfung abgebrochen, weil……

Sofern Sie sich dazu entschließen, vorzeitig aus der klinischen Prüfung auszuscheiden, oder Ihre Teilnahme aus einem anderen der genannten Gründe vorzeitig beendet wird, ist es für Ihre eigene Sicherheit wichtig, dass Sie sich einer empfohlenen abschließenden Kontrolluntersuchung unterziehen (evtl. sonstige studienspezifische Angaben ergänzen, insbesondere zu etwaigen weiteren Maßnahmen zur Sicherheit der Studienteilnehmer). Der Prüfarzt wird mit Ihnen besprechen, ob und wann weitere Kontrolluntersuchungen notwendig sind.

11. Was geschieht mit meinen Daten?

Während der klinischen Prüfung werden medizinische Befunde und persönliche Informationen von Ihnen erhoben und in der Prüfstelle in Ihrer persönlichen Akte niedergeschrieben oder elektronisch gespeichert. Die für die klinische Prüfung wichtigen Daten werden zusätzlich in pseudonymisierter Form gespeichert, ausgewertet und gegebenenfalls weitergegeben. Pseudonymisiert bedeutet, dass keine Angaben von Namen oder Initialen verwendet werden, sondern nur ein Nummern- und/oder Buchstabencode, evtl. mit Angabe des Geburtsjahres. Die Daten sind gegen unbefugten Zugriff gesichert. Eine Entschlüsselung erfolgt nur unter den vom Gesetz vorgeschriebenen Voraussetzungen oder in folgenden Fällen ........... (Angaben aus dem Studienprotokoll). Das Arzneimittelgesetz enthält nähere Vorgaben für den erforderlichen Umfang der Einwilligung in die Datenerhebung und -verwendung. Einzelheiten, insbesondere zur Möglichkeit eines Widerrufs, entnehmen Sie bitte der Einwilligungserklärung, die im Anschluss an diese Probandeninformation abgedruckt ist.



12. Was geschieht mit meinen Blutproben/Gewebeproben/Aufnahmen mit bildgebenden Verfahren (an die jeweilige Studie anpassen)?


Die Blutproben/Gewebeproben/Aufnahmen mit bildgebenden Verfahren werden ausschließlich für diese klinische Prüfung verwendet. Etwaiges Restmaterial wird bei Abschluss der Prüfung vernichtet.

oder:

Die Blutproben/Gewebeproben/Aufnahmen mit bildgebenden Verfahren werden nach Abschluss der Prüfung in folgender Weise verwendet / aufbewahrt: ........... . Erläuterung über Anonymisierung/Pseudonymisierung, soweit voraussehbar Verwendung für andere Zwecke, soweit voraussehbar Dauer und Ort der Aufbewahrung etc., ggf. Verweis auf weiteres Informationsmaterial.

13. An wen wende ich mich bei weiteren Fragen?

Beratungsgespräche an der Prüfstelle

Sie haben stets die Gelegenheit zu weiteren Beratungsgesprächen mit dem auf Seite 1 genannten oder einem anderen Prüfarzt. Kontaktstelle

Es existiert außerdem eine Kontaktstelle bei der zuständigen Bundesoberbehörde. Teilnehmer an klinischen Prüfungen, ihre gesetzlichen Vertreter oder Bevollmächtigten können sich an diese Kontaktstelle wenden:

Alternativ - nur die zuständige Stelle angeben -

entweder:

Bundesinstitut für Arzneimittel und Medizinprodukte Fachgebiet Klinische Prüfung / Inspektionen

Kurt-Georg-Kiesinger-Allee 3

53175 Bonn


oder:

Paul-Ehrlich-Institut Referat Klinische Prüfungen

Paul-Ehrlich-Str. 51-59

63225 Langen




Prüfstelle: ........... Prüfarzt: ........... EUDRACT-Nr. ...........


Einwilligungserklärung

............................................................................................................................ Name des Probanden in Druckbuchstaben

geb. am ........................................ Teilnehmer-Nr. ........................................ Ich bin in einem persönlichen Gespräch durch den Prüfarzt ............................................................................................................................ Name der Ärztin/des Arztes

ausführlich und verständlich über das Prüfmedikament (und ggf. das Vergleichsmedikament) sowie über Wesen, Bedeutung, Risiken und Tragweite der klinischen Prüfung aufgeklärt worden. Ich habe darüber hinaus den Text der Probandeninformation sowie die hier nachfolgend abgedruckte Datenschutzerklärung gelesen und verstanden. Ich hatte die Gelegenheit, mit dem Prüfarzt über die Durchführung der klinischen Prüfung zu sprechen. Alle meine Fragen wurden zufrieden stellend beantwortet. Möglichkeit zur Dokumentation zusätzlicher Fragen seitens des Probanden oder sonstiger Aspekte des Aufklärungsgesprächs:

Ich hatte ausreichend Zeit, mich zu entscheiden. Mir ist bekannt, dass ich jederzeit und ohne Angabe von Gründen meine Einwilligung zur Teilnahme an der Prüfung zurückziehen kann (mündlich oder schriftlich), ohne dass mir daraus Nachteile entstehen.



Datenschutz:

Mir ist bekannt, dass bei dieser klinischen Prüfung personenbezogene Daten, insbesondere medizinische Befunde über mich erhoben, gespeichert und ausgewertet werden sollen. Die Verwendung der Angaben über meine Gesundheit erfolgt nach gesetzlichen Bestimmungen und setzt vor der Teilnahme an der klinischen Prüfung folgende freiwillig abgegebene Einwilligungserklärung voraus, das heißt ohne die nachfolgende Einwilligung kann ich nicht an der klinischen Prüfung teilnehmen. 1. Ich erkläre mich damit einverstanden, dass im Rahmen dieser klinischen Prüfung

personenbezogene Daten, insbesondere Angaben über meine Gesundheit, über mich erhoben und in Papierform sowie auf elektronischen Datenträgern bei/in ........... (Institution/Ort der Aufzeichnung angeben) aufgezeichnet werden. Soweit erforderlich, dürfen die erhobenen Daten pseudonymisiert (verschlüsselt) weitergegeben werden:

a) an ........... , den Sponsor oder eine von diesem beauftragte Stelle zum Zwecke der wissenschaftlichen Auswertung,

b) im Falle eines Antrags auf Zulassung: an den Antragsteller und die für die Zulassung zuständige Behörde ........... (z. B. Bundesinstitut für Arzneimittel und Medizinprodukte),

c) im Falle unerwünschter Ereignisse: an ..........., den Sponsor, an die jeweils zuständige Ethik-Kommission und die zuständige Bundesoberbehörde ........... (hier die Bundesoberbehörde eintragen, z. B. Bundesinstitut für Arzneimittel und Medizinprodukte), sowie von dieser an die Europäische Datenbank.

2. Außerdem erkläre ich mich damit einverstanden, dass autorisierte und zur Verschwiegenheit

verpflichtete Beauftragte des Sponsors sowie die zuständigen Überwachungsbehörden in meine beim Prüfarzt vorhandenen personenbezogenen Daten, insbesondere meine Gesundheitsdaten, Einsicht nehmen, soweit dies für die Überprüfung der ordnungsgemäßen Durchführung der Studie notwendig ist. Für diese Maßnahme entbinde ich den Prüfarzt von der ärztlichen Schweigepflicht.

3. Die Einwilligung zur Erhebung und Verarbeitung meiner personenbezogenen Daten, insbesondere

der Angaben über meine Gesundheit, ist unwiderruflich. Ich bin bereits darüber aufgeklärt worden, dass ich jederzeit die Teilnahme an der klinischen Prüfung beenden kann. Im Fall eines solchen Widerrufs meiner Einwilligung, an der Studie teilzunehmen, erkläre ich mich damit einverstanden, dass die bis zu diesem Zeitpunkt gespeicherten Daten weiterhin verwendet werden dürfen, soweit dies erforderlich ist, um

a) Wirkungen des zu prüfenden Arzneimittels festzustellen,

b) sicherzustellen, dass meine schutzwürdigen Interessen nicht beeinträchtigt werden,

c) der Pflicht zur Vorlage vollständiger Zulassungsunterlagen zu genügen. 4. Ich erkläre mich damit einverstanden, dass meine Daten nach Beendigung oder Abbruch der

Prüfung mindestens zehn Jahre aufbewahrt werden, wie es die Vorschriften über die klinische Prüfung von Arzneimitteln bestimmen. Danach werden meine personenbezogenen Daten gelöscht, soweit nicht gesetzliche, satzungsmäßige oder vertragliche Aufbewahrungsfristen entgegenstehen (vertraglich vereinbarte Fristen müssen hier genannt werden).

5. Ich bin über folgende gesetzliche Regelung informiert: Falls ich meine Einwilligung, an der Studie

teilzunehmen, widerrufe, müssen alle Stellen, die meine personenbezogenen Daten, insbesondere Gesundheitsdaten, gespeichert haben, unverzüglich prüfen, inwieweit die gespeicherten Daten für die in Nr. 3 a) bis c) genannten Zwecke noch erforderlich sind.

Nicht mehr benötigte Daten sind unverzüglich zu löschen. 6. Ich bin damit einverstanden, dass mein Hausarzt ................................................................................................................................... Name

über meine Teilnahme an der klinischen Prüfung informiert wird (falls nicht gewünscht, bitte streichen).



Ich erkläre mich bereit,

an der oben genannten klinischen Prüfung

freiwillig teilzunehmen. Ein Exemplar der Probanden-Information und -Einwilligung (sofern zutreffend: sowie die

Versicherungsbedingungen) sowie die vollständigen Versicherungsunterlagen habe ich erhalten. Ein Exemplar verbleibt im Prüfzentrum. ........................................................................................................................... Name des Probanden in Druckbuchstaben

.................................... ............................................................................... Datum Unterschrift des Probanden

Ich habe das Aufklärungsgespräch geführt und die Einwilligung des Probanden eingeholt. ........................................................................................................................... Name des Prüfarztes/der Prüfärztin in Druckbuchstaben

.................................... ............................................................................... Datum Unterschrift des aufklärenden Prüfarztes/der Prüfärztin


Logo und / oder Addresse der Prüfstelle

Datum Unterschrift Prüfarzt

Prüfarzt: xxx

ERKLÄRUNGEN / BESTÄTIGUNGEN Bestätigung, dass jeder Prüfer durch die für die pharmakologisch-toxikologische Prüfung verantwortlichen Wissenschaftler über deren Ergebnisse und die voraussichtlich mit der klinischen Prüfung verbundenen Risiken informiert worden ist Ich bestätige hiermit, dass ich mich über die pharmakologisch-toxikologischen Ergebnisse und die voraussichtlich mit der klinischen Prüfung verbundenen Risiken informieren werde. Ich werde insbesondere die IB/SmPC/Fachinformationen der in der Studie eingesetzten Arzneimittel sowie den Prüfplan sorgfältig lesen, bevor ich mit studienbezogenen Tätigkeiten beginne. Bestätigung, dass Studienteilnehmer über die Weitergabe ihrer pseudonymisierten Daten im Rahmen der Dokumentations- und Mitteilungspflichten nach § 12 und § 13 der GCP-Verordnung aufgeklärt werden; diese Bestätigung muss eine Erklärung enthalten, dass Studienteilnehmer, die der Weitergabe nicht zustimmen, nicht in die klinische Prüfung eingeschlossen werden Ich bestätige hiermit, dass die Studienteilnehmer über die Weitergabe ihrer pseudonymisierten Daten aufgeklärt werden. Studienteilnehmer, die einer Weitergabe der Daten nicht zustimmen, werden nicht in die Studie eingeschlossen. Erklärung zur Einhaltung des Datenschutzes Ich erkläre hiermit, dass insbesondere durch Pseudonymisierung der Daten sichergestellt wird, dass die personenbezogenen Daten geschützt bleiben. Beim Umgang mit personenbezogenen Daten werden die Grundsätze des Datenschutzes beachtet. Erklärung zur Einbeziehung möglicherweise vom Sponsor oder Prüfer abhängiger Personen Ich erkläre hiermit, dass vom Sponsor oder Prüfer abhängige Personen grundsätzlich nicht in die klinische Studie eingeschlossen werden. Angaben zu möglichen wirtschaftlichen und anderen Interessen der Prüfer im Zusammenhang mit den Prüfpräparaten Ich bestätige hiermit, dass von Seiten des Prüfers keine wirtschaftlichen und andere Interessen im Zusammenhang mit den Prüfpräparaten bestehen.


Logo and / or address of sponsor

Letter of Authorisation

Name, address of Sponsor, responsible for conduct of clinical trial Protocol Number xxx (EudraCT Number: xxx), hereby authorizes Name / Address of CRO to act as an applicant on our behalf for the request for authorisation to the Competent Authority and for opinion of the Ethics Committees in the community in accordance with the national laws of Germany and also in accordance with Directive 2001/20/EC. Name: xxx Title: xxx ________________ ________________________ Date Signature


Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) Fachregistratur „Klinische Prüfungen“ Kurt-Georg-Kiesinger-Allee 3 53175 Bonn

Antrag auf Genehmigung einer klinischen Prüfung bei der zuständigen Bundesoberbehörde nach § 40 Abs. 1 Satz 2 AMG sowie § 7 GCP-V

ttmmjjjj

EudraCT-Nr.:

Prüfplan-Code: Titel Sehr geehrte Damen und Herren, hiermit bitten wir um Genehmigung zur Durchführung der oben genannten klinischen Prüfung. Nachfolgend machen wir dazu folgende Angaben: Sponsor:

Vertreter in der EU: falls zutreffend Antragsteller im Auftrag des Sponsors:

Prüfstelle:

Hauptprüfer:

Labor:

alle beteiligten Labors nennen Zuständige Ethikkommission: Hinweise und Besonderheiten der klinischen Prüfung: Besonderheiten nennen (DZ, Abs. 8) Plan zur Weiterbehandlung und medizinischen Betreuung der betroffenen Personen nach dem Ende der klinischen Prüfung (§ 7 Abs. 2 Nr. 13 GCP-V): Behandlungsplan einfügen (DZ, Abs. 15) Begründung für die Geschlechterverteilung: Begründung nennen (DZ, Abs. 13)


Bestätigungen: Hiermit bestätigen wir, dass

• gemäß §7 (2) 15 GCP-V betroffene Personen über die Weitergabe ihrer pseudonymisierten Daten im Rahmen der Dokumentations- und Mitteilungspflichten nach § 12 Abs. 4 und § 13 Abs. 1 GCP-V an die dort genannten Empfänger aufgeklärt werden, mit einer Erklärung darüber, dass betroffene Personen, die der Weitergabe nicht zustimmen, nicht in die klinische Prüfung eingeschlossen werden,

• gemäß § 5 (2) 2 GCP-V die Telefonnummer(n) des Sponsors und der CRO in Begleitdokumente (Patienteninformation / Patientenkarte) aufgenommen werden, nur, wenn nicht auf Labeln enthalten

• gemäß § 5 (2) 10 GCP-V der Prüfplancode zur Identifizierung der klinischen Prüfung, der Prüfstelle, des Prüfers und des Sponsors in Begleitdokumente (Patienteninformation / Patientenkarte) aufgenommen wird, nur, wenn nicht auf Labeln enthalten

• gemäß § 5 (2) 11 GCP-V die von der europäischen Datenbank vergebene EudraCT-Nummer in Begleitdokumente (Patienteninformation / Patientenkarte) aufgenommen wird, nur, wenn nicht auf Labeln enthalten

• gemäß § 5 (2) 12 GCP-V ein Identifizierungscode der betroffenen Person, und, sofern erforderlich, die Kennzeichnung der Einnahmesequenz, in Begleitdokumente (Patienteninformation / Patientenkarte) aufgenommen werden, nur, wenn nicht auf Labeln enthalten

• gemäß § 5(2)15 GCP-V die Prüfpräparate nicht an die Studienteilnehmer ausgehändigt werden und somit der Hinweis zur für Kinder unzugänglichen Aufbewahrung entfallen kann, nur, wenn nicht auf Labeln enthalten und keine Abgabe erfolgt

• gemäß § 5 (2)16 GCP-V die Prüfpräparate nicht an die Studienteilnehmer ausgehändigt werden und somit die Angaben für die Rückgabe entfallen können, nur, wenn nicht auf Labeln enthalten und keine Abgabe erfolgt

• ausschließlich Ärzte als Prüfer in dieser Studie eingesetzt werden. Zur Beratung unseres Antrags senden wir Ihnen folgende Unterlagen in 4-facher Ausfertigung:

1. Anschreiben vom 2. Antrag (CTA) vom mit Unterschriftsseite 3. Bestätigung der EudraCT-Nr. 4. Vollmacht des Sponsors 5. Prüfplan

a) Prüfplan, Version vom b) Unterschriften

6. Dossier zum Prüfpräparat a) IMPD Non-Clinical b) IMPD Clinical c) IMPD Quality d) IMPD Placebo e) Benefits and Risks Assessment, Version vom f) TSE-Certificate g) SUSAR Line Listing, Periode bis

7. IB / Fachinformationen / SmPC a) Investigator’s Brochure Präparat, Edition vom b) Fachinformation Präparat, Stand c) Summary of Product Characteristics (SmPC) Präparat, Stand

8. Labelentwürfe a) Labelentwürfe der Prüfsubstanzen b) Anmerkungen zum Labeling c) Patientenkarte

9. Herstellungserlaubnis a) Herstellungserlaubnis Name b) Herstellungs- und Einfuhrerlaubnis Name c) GMP Zertifikat Name d) Einfuhrerlaubnis Name

ggf. Hinweis zur Herstellungserlaubnis:

Die Herstellungserlaubnis von wird beigefügt, da im Prüfzentrum (Aktion beschreiben). Die Freigabe der Prüfsubstanzen erfolgt durch .


ggf. Hinweis auf Studien mit gleicher Prüfmedikation: xxx war bereits Gegenstand der genehmigten klinischen Prüfungen: xxx (Vorlage-Nummer: xxx) xxx ist außerdem Gegenstand der eingereichten klinischen Prüfungen: xxx (Vorlage-Nummer: xxx) Die in Papierform eingereichten Dokumente erhalten Sie gleichzeitig in elektronischer Form im xml- und pdf-Format auf CD-ROM. Wir bestätigen, dass beide Versionen identisch sind. Für Rückfragen stehen wir Ihnen jederzeit gerne zur Verfügung. Mit freundlichen Grüßen Name

Regulatory Affairs Manager


Label für IMP

Interner Studien Code: Probanden Nr.:

Protokoll-Nr.:

Name des Arzneistoffs

z.B. X Tbl. à X mg Arzneistoff oder Placebo

Darreichungsform: X Tabletten / Kapseln / Stück etc.

Dosierungsanleitung: z B: täglich morgens eine Tablette vor der Mahlzeit einnehmen

oder Dosierung gemäß Prüfplan

Ch.-B.: Verwendbar bis: MM.JJJJ

Eudra-CT-Nummer:

Lagerung: z.B. Trocken, unter 25°C, vor Licht schützen

Für Kinder unzugänglich aufbewahren

Zur klinischen Prüfung bestimmt

Name und Anschrift , Tel Nr. des Sponsors und/oder der CRO und/oder des Prüfers:


Anzeige einer klinischen Prüfung gemäß § 67 Abs. 1 und 3 AMG und § 12 Abs. 1-3 GCP-V bei der zuständigen Landesbehörde

A n z e i g e f o r m u l a r k l i n i s c h e P r ü f u n g Seite 1 von 1

Version 06

1. Vollständiger Titel des Prüfplans (einschl. Zielsetzung)

Prüfplancode EudraCT-Nr.

2. An (Name und Anschrift der zuständigen Behörde)

3. Name (ggf. Firmenbezeichnung) und

Anschrift, Telefonnummer und E-Mailadresse des Anzeigenden

Art der anzeigenden Einrichtung

Prüfer (§ 12 GCP-V)

Sponsor

Vertreter des Sponsors

Auftragsforschungsinstitut (CRO)

Prüflaboratorium

sonstiges:

Falls zutreffend: Der Prüfer hat dem Sponsor die Durchführung der Anzeige bei der zuständigen Behörde gemäß §12(3) GCP-V übertragen.

4. Falls abweichend vom Anzeigenden gesonderte Rechnungsanschrift




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5. Grund der Anzeige

Anmeldung (s. Ziffer 1) Abmeldung der Gesamtstudie *2

Abmeldung von Prüfstellen gemäß Ziffer 6*2

*2 Angabe des Abmeldedatums (Ziffer 14)

Änderungsanzeige*

*Erläuterung zum Gegenstand der Änderungsanzeige (z.B. An-/ Abmeldung von Prüfern, genehmigungspflichtige Amendments, Studiendauer o.ä.):

6. Prüfer (Name und Berufsbezeichnung) und Prüfstellen im Zuständigkeitsbereich

der Behörde zu Ziffer 2 (ggf. zusätzliche Auflistung als Anlage 6a beifügen)

6.1 Anschrift der Prüfstelle Hauptprüfer Weitere Prüfer









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7. Bezeichnung der zuständigen Bundesoberbehörde sowie Datum der Genehmigung

Bundesinstitut für Arzneimittel und Medizinprodukte

Paul-Ehrlich-Institut

Datum der Genehmigung

BfArM- bzw. PEI-Nummer

Daten von Genehmigungen nachträglicher Änderungen nach § 10 Abs. 1 GCP-V

Gegenstand der Änderung (Version, Amendment vom etc.) Genehmigungsdatum

genehmigt am

genehmigt am

genehmigt am

genehmigt am

genehmigt am

8. Bezeichnung und Anschrift der nach § 42 Abs. 1 Satz 1 oder 2 AMG zuständigen

Ethikkommission

Datum der zustimmenden Bewertung:

Daten von Genehmigungen nachträglicher Änderungen nach § 10 Abs. 1 GCP-V

Gegenstand der Änderung (Version, Amendment vom etc.) Genehmigungsdatum

genehmigt am

genehmigt am

genehmigt am

genehmigt am

genehmigt am

9. Bei multizentrischer Prüfung Name und Anschrift des Leiters der klinischen

Prüfung




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10. Bezeichnung und Anschrift der für den Prüfer und die Prüfstelle zuständigen beteiligten Ethik-Kommission (ggf. zusätzliche Auflistung als Anlage 10a beifügen)

Ziffer Ethik-Kommission Datum der zustimmenden Bewertung

10.1 genehmigt am

10.2 genehmigt am

10.3 genehmigt am

10.4 genehmigt am

10.5 genehmigt am

10.6 genehmigt am

11. Name, Anschrift, Telefonnummer, E-Mailadresse und Ansprechpartner des

Sponsors

11.1 ggf. Name, Anschrift, Telefonnummer, E-Mailadresse und Ansprechpartner seines in der EU/EWR niedergelassenen Vertreters

11.2 ggf. Name, Anschrift, Telefonnummer, E-Mailadresse und Ansprechpartner anderer eingebundener Einrichtungen (ggf. zusätzliche Auflistung als Anlage 11a beifügen)

11.2.1 CRO Labor Sonstiges







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12. zu prüfendes Anwendungsgebiet

13. Art der klinischen Prüfung und ihrer Durchführung

Phase

Art der klinischen Prüfung (Design)

Durchführung monozentrisch multizentrisch

besondere Merkmale betroffener Personen (entspr. § 41 AMG)

14. geplanter Beginn und voraussichtliches Ende der klinischen Prüfung

geplanter Beginn (Monat/Jahr)

a) in der/den Prüfstelle(n) nach Nr. 6

b) der Gesamtstudie im Geltungsbereich des AMG

voraussichtliches Ende (Monat/Jahr)

a) in der/den Prüfstelle(n) nach Nr. 6

b) der Gesamtstudie im Geltungsbereich des AMG

Bei Abmeldungen: Ende der Gesamtstudie bzw. der klinischen Prüfung in den unter Ziffer 6 aufgeführten Prüfstellen (Monat/Jahr)

15. Bezeichnung, Stärke, Darreichungsform, arzneilich wirksame Bestandteile und Art

der Anwendung des Prüfpräparates

Bezeichnung

Stärke

Darreichungsform

Wirksame Bestandteile (ggf. Code)

Art der Anwendung




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16. Informationen, ob Regelungen des Betäubungsmittelrechts, des Gentechnikrechts oder des Strahlenschutzrechts zu beachten sind oder es sich um ein somatisches Gentherapeutikum oder Gendiagnostikum handelt

Das Prüfpräparat unterliegt Regelungen

des BtM-Rechts des Strahlenschutzrechts des Gentechnikrechts

Das Prüfpräparat ist

ein somatisches Gentherapeutikum Gendiagnostikum

17. Anzahl und Art der mitgeführten Vergleichspräparate

Anzahl

Art (Bezeichnung, Darreichungsform)

18. Anzeige der Rekonstitution von Prüfpräparaten gemäß § 67 Abs. 1 AMG

Im Rahmen der Durchführung der klinischen Prüfung werden Prüfpräparate rekonstituiert:

Ja Nein

Falls ja: Name, Berufsbezeichnung und Anschrift der für die Rekonstitution verantwortlichen Person

Datum Name in Blockschrift

Unterschrift


Substantial Amendment Notification Form (Cf. Section 3.7.b of the Detailed guidance on the

request to the competent authorities for authorisation of a clinical trial on a medicinal product

for human use, the notification of substantial amendments and the declaration of the end of the

trial1)

NOTIFICATION OF A SUBSTANTIAL AMENDMENT TO A CLINICAL TRIAL ON A

MEDICINAL PRODUCT FOR HUMAN USE TO THE COMPETENT AUTHORITIES AND

FOR OPINION OF THE ETHICS COMMITTEES IN THE EUROPEAN UNION

For official use:

Date of receiving the request :

Grounds for non acceptance/ negative opinion : o

Date :

Date of start of procedure: Authorisation/ positive opinion : o

Date :

Competent authority registration number of the trial:

Ethics committee registration number of the trial :

Withdrawal of amendment application o

Date :

To be filled in by the applicant:

This form is to be used both for a request to the Competent Authority for authorisation of a

substantial amendment and to an Ethics Committee for its opinion on a substantial amendment.

Please indicate the relevant purpose in Section A.

A TYPE OF NOTIFICATION

A.1 Member State in which the substantial amendment is being submitted:

A.2 Notification for authorisation to the competent authority: oooo

A.3 Notification for an opinion to the ethics committee: oooo

B TRIAL IDENTIFICATION (When the amendment concerns more than one trial, repeat this

form as necessary.)

B.1 Does the substantial amendment concern several trials involving the same IMP?2 yes o no o

B.1.1 If yes repeat this section as necessary.

B.2 Eudract number:

B.3 Full title of the trial :

B.4 Sponsor’s protocol code number, version, and date:

C IDENTIFICATION OF THE SPONSOR RESPONSIBLE FOR THE REQUEST

C.1 Sponsor

C.1.1 Organisation:

C.1.2 Name of person to contact:

C.1.3 Address :

C.1.4 Telephone number :

C.1.5 Fax number :

C.1.6 e-mail:

C.2 Legal representative3 of the sponsor in the European Union for the purpose of this trial (if different

from the sponsor)

C.2.1 Organisation:

C.2.2 Name of person to contact:

C.2.3 Address :

C.2.4 Telephone number :

C.2.5 Fax number :

C.2.6 e-mail:

1 OJ, C82, 30.3.2010, p. 1; hereinafter referred to as 'detailed guidance CT-1'.

2 Cf. Section 3.7. of the detailed guidance CT-1.

3 As stated in Article 19 of Directive 2001/20/EC.


D APPLICANT IDENTIFICATION (please tick the appropriate box)

D.1 Request for the competent authority D.1.1 Sponsor o

D.1.2 Legal representative of the sponsor o

D.1.3 Person or organisation authorised by the sponsor to make the application. o

D.1.4 Complete below:

D.1.4.1 Organisation :

D.1.4.2 Name of person to contact :

D.1.4.3 Address :

D.1.4.4 Telephone number :

D.1.4.5 Fax number :

D.1.4.6 E-mail

D.2 Request for the Ethics Committee

D.2.1 Sponsor o

D.2.2 Legal representative of the sponsor o

D.2.3 Person or organisation authorised by the sponsor to make the application. o

D.2.4 Investigator in charge of the application if applicable4:

• Co-ordinating investigator (for multicentre trial) o

• Principal investigator (for single centre trial): o

D.2.5 Complete below

D.2.5.1 Organisation :

D.2.5.2 Name :

D.2.5.3 Address :

D.2.5.4 Telephone number :

D.2.5.5 Fax number :

D.2.6 E-mail :

E SUBSTANTIAL AMENDMENT IDENTIFICATION

E.1 Sponsor’s substantial amendment code number, version, date for the clinical trial concerned: ( )

E.2 Type of substantial amendment

E.2.1 Amendment to information in the CT application form yes o no o

E.2.2 Amendment to the protocol yes o no o

E.2.3 Amendment to other documents appended to the initial application form yes o no o

E.2.3.1 If yes specify:

E.2.4 Amendment to other documents or information: yes o no o

E.2.4.1 If yes specify: E.2.5 This amendment concerns mainly urgent safety measures already implemented

5 yes o no o

E.2.6 This amendment is to notify a temporary halt of the trial6 yes o no o

E.2.7 This amendment is to request the restart of the trial7 yes o no o

E.3 Reasons for the substantial amendment:

E.3.1 Changes in safety or integrity of trial subjects yes oooo no oooo

E.3.2 Changes in interpretation of scientific documents/value of the trial yes oooo no oooo

E.3.3 Changes in quality of IMP(s) yes oooo no oooo

E.3.4 Changes in conduct or management of the trial yes oooo no oooo

E.3.5 Change or addition of principal investigator(s), co-ordinating investigator yes oooo no oooo

E.3.6 Change/addition of site(s) yes oooo no oooo

E.3.7 Other change yes oooo no oooo

E.3.7.1 If yes, specify:

4 According to national legislation.





E.3.8 Other case yes oooo no oooo

E.3.8.1 If yes, specify

E.3.8.2

E.4 Information on temporary halt of trial8

E.4.1 Date of temporary halt (YYYY/MM/DD)

E.4.2 Recruitment has been stopped yes o no o

E.4.3 Treatment has been stopped yes o no o

E.4.4 Number of patients still receiving treatment at time of the temporary halt in the MS concerned

by the amendment ( )

E.4.5 Briefly describe (free text):

• Justification for a temporary halt of the trial

• The proposed management of patients receiving treatment at time of the halt (free text).

The consequences of the temporary halt for the evaluation of the results and for overall risk benefit assessment

of the investigational medicinal product (free text).

F DESCRIPTION OF EACH SUBSTANTIAL AMENDMENT9 (free text):

Previous and new wording in

track change modus

New wording Comments/explanation/reasons

for substantial amendment

G CHANGE OF CLINICAL TRIAL SITE(S)/INVESTIGATOR(S) IN THE MEMBER STATE

CONCERNED BY THIS AMENDMENT

G.1 Type of change

G.1.1 Addition of a new site G.1.1.1 Principal investigator (provide details below)

G.1.1.1.1 Given name

G.1.1.1.2 Middle name (if applicable)

G.1.1.1.3 Family name

G.1.1.1.4 Qualifications (MD……..)

G.1.1.1.5 Professional address

G.1.2 Removal of an existing site G.1.2.1 Principal investigator (provide details below)

G.1.2.1.1 Given name

G.1.2.1.2 Middle name (if applicable)

G.1.2.1.3 Family name

G.1.2.1.4 Qualifications (MD……..)

G.1.2.1.5 Professional address

G.1.3 Change of co-ordinating investigator (provide details below of the new coordinating investigator)

G.1.3.1 Given name

G.1.3.2 Middle name

G.1.3.3 Family name

G.1.3.4 Qualification (MD……….)

G.1.3.5 Professional address

G.1.3.6 Indicate the name of the previous co-ordinating investigator:

G.1.4 Change of principal investigator at an existing site (provide details below of the new principal

investigator)

G.1.4.1 Given name

G.1.4.2 Middle name

G.1.4.3 Family name

G.1.4.4 Qualifications (MD……..)

G.1.4.5 Professional address

G.1.4.6 Indicate the name of the previous principal investigator:


9 Cf. Section 3.7.c. of the detailed guidance CT-1. The sponsor may submit this documentation on a separate

sheet.


H CHANGE OF INSTRUCTIONS TO CA FOR FEEDBACK TO SPONSOR

H.1 Change of e-mail contact for feedback on application*

H.2 Change to request to receive an .xml copy of CTA data o yes o no

H.2.1 Do you want a .xml file copy of the CTA form data saved on EudraCT? o yes o no

H.2.1.1 If yes provide the e-mail address(es) to which it should be sent (up to 5 addresses):

H.2.2 Do you want to receive this via password protected link(s)10

? o yes o no

If you answer no to question H.2.2 the .xml file will be transmitted by less secure e-mail link(s)

H.2.3 Do you want to stop messages to an email for which they were previously requested? o yes o no

H.2.3.1 If yes provide the e-mail address(es) to which feedback should no longer be sent:

(*This will only come into effect from the time at which the request is processed in EudraCT).

I LIST OF THE DOCUMENTS APPENDED TO THE NOTIFICATION FORM (cf. Section 3.7 of

detailed guidance CT-1)

Please submit only relevant documents and/or when applicable make clear references to the ones

already submitted. Make clear references to any changes of separate pages and submit old and new

texts. Tick the appropriate box(es).

I.1 Cover letter o

I.2 Extract from the amended document in accordance with Section 3.7.c. of detailed guidance CT-1 (if not

contained in Part F of this form) o

I.3 Entire new version of the document11

o

I.4 Supporting information o

I.5 Revised .xml file and copy of initial application form with amended data highlighted o

I.6 Comments on any novel aspect of the amendment if any :

J SIGNATURE OF THE APPLICANT IN THE MEMBER STATE

J.1 I hereby confirm that/ confirm on behalf of the sponsor that (delete which is not applicable)

• The above information given on this request is correct;

• The trial will be conducted according to the protocol, national regulation and the principles of good

clinical practice; and

• It is reasonable for the proposed amendment to be undertaken.

J.2 APPLICANT OF THE REQUEST FOR THE COMPETENT AUTHORITY(as stated in section D.1):o

J.2.1 Signature 12

:

J.2.2 Print name :

J.2.3 Date :

J.3 APPLICANT OF THE REQUEST FOR THE ETHICS COMMITTEE (as stated in section D.2): o

J.3.1 Signature 13

:

J.3.2 Print name:

J.3.3 Date :

10

This requires a EudraLink account. (See https://eudract.ema.europa.eu/ for details) 11

Cf. Section 3.7.c. of the detailed guidance CT-1. 12

On an application to the Competent Authority only, the applicant to the Competent Authority needs to sign. 13

On an application to the Ethics Committee only, the applicant to the Ethics Committee needs to sign.


Beschluss 4

Versand von Amendments bei multizentrischen Studien (Stand 12.11.2005, in der auf Grund der Beschlüsse der 9. Sommertagung am 14.Juni 2008 geänderten Fassung)

Bewertungspflichtige nachträgliche Änderungen (Substantial Amendments)

Verfahren

Unterlagen zu bewertungspflichtigen nachträglichen Änderungen (Definition siehe GCP-V § 10 Abs. 1) sendet der Antragsteller zur Bewertung zeitgleich an die feder-führende und an die beteiligten Ethik-Kommissionen (jeweils max. 2x Hard Copy und 1x elektronisch).

Änderungen von Prüfern in einer Prüfstelle „Die Änderung des Leiters der klinischen Prüfung, des Hauptprüfers oder des einzigen Prüfers in einer Prüfstelle oder die Meldung zusätzlicher Prüfer sind bewertungspflichtige, nachträgliche Änderungen (GCP-V § 3 Abs. 2c und § 10 Abs. 1 Ziffer 3).“

Nichtbewertungspflichtige nachträgliche Änderungen (Non-Substantial Amendments)

• Unterlagen zu nichtbewertungspflichtigen nachträglichen Änderungen gehen nur an die federführende Ethik-Kommission (1x Papierversion und 1x elektronische Version).

• Nichtbewertungspflichtige nachträgliche Änderungen sind gemäß EU-Guidances (ENTR/CT1 Kap. 4.2.2 und ENTR/CT2 Kap. 6.2.1) nicht vorlagepflichtig. Sie sind jedoch sorgfältig zu dokumentieren und beim Sponsor und der Prüfstelle zu archi-vieren. Die Ethik-Kommission kann jederzeit die Vorlage anfordern.

• Der Arbeitskreis der Ethik-Kommissionen fordert immer die Vorlage folgender nichtbewertungspflichtiger nachträglicher Änderungen an:

- Änderungen in Unterlagen, die sich an die Studienteilnehmer richten (Informationsschriften, Fragebogen, etc.)


Declaration of the End of Trial Form (cf. Section 4.2.1 of the Detailed guidance on the request

to the competent authorities for authorisation of a clinical trial on a medicinal product for

human use, the notification of substantial amendments and the declaration of the end of the

trial1)

NOTIFICATION OF THE END OF A CLINICAL TRIAL OF A MEDICINE FOR HUMAN USE

TO THE COMPETENT AUTHORITY AND THE ETHICS COMMITTEE

For official use

Date of receipt :

Competent authority registration number :

Ethics committee registration number:

To be filled in by the applicant

A MEMBER STATE IN WHICH THE DECLARATION IS BEING MADE :

B TRIAL IDENTIFICATION

B.1 EudraCT number : (..)

B.2 Sponsor’s protocol code number: (..)

B.3 Full title of the trial :

C APPLICANT IDENTIFICATION (please tick the appropriate box)

C.1 DECLARATION FOR THE COMPETENT AUTHORITY o C.1.1 Sponsor o

C.1.2 Legal representative of the sponsor o

C.1.3 Person or organisation authorised by the sponsor to make the application. o

C.1.4 Complete below:

C.1.4.1 Organisation :

C.1.4.2 Name of person to contact :

C.1.4.3 Address :

C.1.4.4 Telephone number :

C.1.4.5 Fax number :

C.1.4.6 E-mail

C.2 DECLARATION FOR THE ETHICS COMMITTEE o C.2.1 Sponsor o

C.2.2 Legal representative of the sponsor o

C.2.3 Person or organisation authorised by the sponsor to make the application. o

C.2.4 Investigator in charge of the application if applicable2:

• Co-ordinating investigator (for multicentre trial): o

• Principal investigator (for single centre trial): o

C.2.5 Complete below :

C.2.5.1 Organisation:

C.2.5.2 Name :

C.2.5.3 Address :

C.2.5.4 Telephone number :

C.2.5.5 Fax number :

C.2.5.6 E-mail :

D END OF TRIAL

D.1 Date of the end of the complete trial in all countries concerned by the trial?

D.1.1 (YYYY/MM/DD):

1 OJ, C82, 30.3.2010, p. 1; hereinafter referred to as 'detailed guidance CT-1'.

2 According to national legislation.


D.2 Is it an early termination?

3 yes o no o

D.2.1 If yes, give date (YYYY/MM/DD):

D.2.2 Briefly describe in an annex (free text):

D.2.2.1 The justification for early termination of the trial;

D.2.2.2 Number of patients still receiving treatment at time of early termination in the MS concerned by the

declaration and their proposed management;

D.2.2.3 The consequences of early termination for the evaluation of the results and for overall risk benefit

assessment of the investigational medicinal product.

E SIGNATURE OF THE APPLICANT IN THE MEMBER STATE

E.1 I hereby confirm that/confirm on behalf of the sponsor that (delete which is not applicable):

• The above information given on this declaration is correct; and

• That the clinical trial summary report will be submitted within the applicable deadlines in

accordance with the applicable guidance by the Commission.4

E.2 APPLICANT TO THE COMPETENT AUTHORITY (as stated in C.1) o

E.2.1 Date :

E.2.2 Signature :

E.2.3 Print name:

E.3 APPLICANT TO THE ETHICS COMMITTEE (as stated in C.2) : o

E.3.1 Date :

E.3.2 Signature :

E.3.3 Print name:


4 Section 4.3. of the detailed guidance CT-1.